Cycloalkyl Lactame Derivatives As Inhibitors Of 11-Beta-Hydroxysteroid Dehydrogenase 1

ABSTRACT

This invention relates to novel compounds of the Formula (I), any of the formulas I 1 -I 26  Ia 1-3 -Ij 1-3  or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 61/065,890, filed on Feb. 15, 2008, the entire teachings of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), pharmaceutical compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Glucocorticoids, such as cortisol (hydrocortisone), are steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism, and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.

Until recently, the major determinants of glucocorticoid action were attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues. Recently, a fourth determinant of glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 11β-hydroxysteroid dehydrogenase (11β-HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as 11-beta-HSD type 1, 11betaHSD1, HSD11B1, HDL, and HSD11L) and 11β-HSD2. 11β-HSD1 is a bi-directional oxidoreductase that regenerates active cortisol from inactive 11-keto forms, whereas 11β-HSD2 is a unidirectional dehydrogenase that inactivates biologically active cortisol by converting it into cortisone.

The two isoforms are expressed in a distinct tissue-specific fashion, consistent with the differences in their physiological roles. 11β-HSD1 is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium. In adipose tissue, increased cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity. In the eye, 11β-HSD1 may regulate intraocular pressure and may contribute to glaucoma; some data suggest that inhibition of 11β-HSD1 may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevstev et al. (1997), Proc. Natl. Acad. Sci. USA 94(26):14924-9). Although 11β-HSD1 catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreduction reaction, 11β-HSD1 acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active cortisol from inert cortisone (Low et al. (1994) J. Mol. Endocrin. 13: 167-174). In contradistinction, 11β-HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines. 11β-HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of cortisol to cortisone (Albiston et al. (1994) Mol. Cell, Endocrin. 105: R11-R17), and has been shown to protect the MR from glucocorticoid excess (e.g., high levels of receptor-active cortisol) (Blum, et al. (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-216).

Mutations in either the 11β-HSD1 or the 11β-HSD2 genes result in human pathology. For example, individuals with mutations in 11β-HSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as ‘SAME’) characterized by hypertension, hypokalemia, and sodium retention (Edwards et al. (1988) Lancet 2: 986-989; Wilson et al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in 11β-HSD1 and in the gene encoding a co-localized NADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD); these individuals present with ACTH-mediated androgen excess (hirsutism, menstrual irregularity, hyperandrogenism), a phenotype resembling polycystic ovary syndrome (PCOS) (Draper et al. (2003) Nat. Genet. 34: 434-439).

Notably, disruption of homeostasis in the HPA axis by either deficient or excess secretion or action results in Cushing's syndrome or Addison's disease, respectively (Miller and Chrousos (2001) Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4^(th) Ed.: 387-524). Patients with Cushing's syndrome or receiving glucocorticoid therapy develop reversible visceral fat obesity. The phenotype of Cushing's syndrome patients closely resembles that of Reaven's metabolic syndrome (also known as Syndrome X or insulin resistance syndrome), the symptoms of which include visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven (1993) Ann. Rev. Med. 44: 121-131). Although the role of glucocorticoids in human obesity is not fully characterized, there is mounting evidence that 11β-HSD1 activity plays an important role in obesity and metabolic syndrome (Bujalska et al. (1997) Lancet 349: 1210-1213); (Livingstone et al. (2000) Endocrinology 131: 560-563; Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al. (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin. Endocrinol. Metab. 88: 3983-3988).

Data from studies in mouse transgenic models supports the hypothesis that adipocyte 11β-HSD1 activity plays a central role in visceral obesity and metabolic syndrome (Alberts et al. (2002) Diabetologia. 45(11): 1526-32). Over-expression in adipose tissue of 11β-HSD1 under the control of the aP2 promoter in transgenic mice produced a phenotype remarkably similar to human metabolic syndrome (Masuzaki et al. (2001) Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). Moreover, the increased activity of 11β-HSD1 in these mice is very similar to that observed in human obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421). In addition, data from studies with 11β-HSD1-deficient mice produced by homologous recombination demonstrate that the loss of 11β-HSD1 leads to an increase in insulin sensitivity and glucose tolerance due to a tissue-specific deficiency in active glucocorticoid levels (Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938).

The published data supports the hypothesis that increased expression of 11β-HSD1 contributes to increased local conversion of cortisone to cortisol in adipose tissue and hence that 11β-HSD1 plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17). Therefore, 11β-HSD1 is a promising pharmaceutical target for the treatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore, inhibition of 11β-HSD1 activity may prove beneficial in treating numerous glucocorticoid-related disorders. For example, 11β-HSD1 inhibitors could be effective in combating obesity and/or aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938). In addition, inhibition of 11β-HSD1 activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin. Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275: 34841-34844).

Furthermore, given that inter-individual differences in general cognitive function have been linked to variability in the long-term exposure to glucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1: 69-73) and dysregulation of the HPA axis resulting in chronic exposure to glucocorticoid excess in certain brain subregions has been theorized to contribute to the decline of cognitive function (McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205-216), one might predict that inhibition of 11β-HSD1 could reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression. Notably, it is known that stress and glucocorticoids influence cognitive function (de Quervain et al. (1998) Nature 394: 787-790); and it has been shown that 11β-HSD1, through its control of glucocorticoid action in the brain, may have effects on neurotoxicity (Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000) Neuroendocrinol. 18:49-99).

There is also evidence that glucocorticoids and 11β-HSD1 play a role in regulation of in intra-ocular pressure (IOP) (Stokes et al. (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042); if left untreated, elevated IOP can lead to partial visual field loss and eventually blindness. Thus, inhibition of 11β-HSD1 in the eye could reduce local glucocorticoid concentrations and IOP, and 11β-HSD1 hence could potentially be used to treat glaucoma and other visual disorders.

Transgenic aP2-11βHSD1 mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Moreover, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin II and aldosterone; and treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This suggests that hypertension may be caused or exacerbated by 11β-HSD1 activity. Thus, 11β-HSD1 inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders. Inhibition of 11β-HSD1 in mature adipocytes is also expected to attenuate secretion of plasminogen activator inhibitor 1 (PAI-1), which is an independent cardiovascular risk factor (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84: 4097-4105).

Glucocorticoids can have adverse effects on skeletal tissues; and prolonged exposure to even moderate glucocorticoid doses can result in osteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447). In addition, 11β-HSD1 has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper et al. (2000) Bone 27: 375-381), and the 11β-HSD1 inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23: 119-125). Thus, inhibition of 11β-HSD1 is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis.

11β-HSD1 inhibitors may also be useful for immunomodulation. Although glucocorticoids are perceived to suppress the immune system, in actuality, there is a complex, dynamic interaction between the HPA axis and the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581). Glucocorticoids play a role in modulating the balance between cell-mediated and humoral immune response, with high glucocorticoid activity normally associated with a humoral response. Inhibition of 11β-HSD1 therefore can be used a means of shifting the immune response towards a cell-mediated response. Certain disease states, such as tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune responses that are biased towards a humoral response whereas the more effective immune response may be a cell-mediated response. Hence, 11β-HSD1 inhibitors may be useful for treating such diseases.

It has been reported that glucocorticoids inhibit wound healing, especially in diabetic patients with ulcers (Bitar et al. (1999) J. Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar (2000) Surgery 127: 687-695; Bitar (1998) Am. J. Pathol. 152: 547-554). Patients that exhibit impaired glucose tolerance and/or type 2 diabetes often also have impaired wound healing. Glucocorticoids have been shown to increase the risk of infection and delay wound healing (Anstead (1998) Adv. Wound Care 11:277-285). Moreover, there is a correlation between elevated levels of cortisol in wound fluid and non-healing wounds (EP Patent App. No. 0 902 288). Recent published patent applications have suggested that certain 11β-HSD1 inhibitors may be useful for promoting wound healing (PCT/US2006/043,951).

As evidenced herein, there is a continuing need for new and improved drugs that inhibit 11β-HSD1. The novel compounds of the instant invention are effective inhibitors of 11β-HSD1.

SUMMARY OF THE INVENTION

It has now been found that compounds of Formula I or pharmaceutically acceptable salts thereof, are effective inhibitors of 11β-HSD1. Formula I and its constituent members are defined herein as follows:

R is

R¹ is (a) absent or (b) is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl, wherein each is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R⁴, R⁴O—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino;

A¹ is (a) a bond, or (b) (C₁-C₃)alkylene, CH₂CH₂O, wherein the oxygen is attached to Cy¹, or CH₂C(═O), wherein the carbonyl carbon is attached to Cy¹;

Cy¹ is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl; (C₁-C₆)alkylcarbonyl; (C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl, di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminosulfonyl, di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl and di(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; provided that if (a) t is 2 and Q is O or CH₂ or t is 1 and Q is 0, (b) A¹ is CH₂ optionally substituted with R₁ and (c) A² is a bond, then Cy² is meta or para to the ring atom of Cy¹ that is bonded to A¹ and the aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, represented by Cy¹ is not substituted with bromine, iodine, amino, halo(C₁-C₆)alkyl at a ring atom ortho to the carbon atom bounded to A¹;

A² is (a) a bond, O, S or NR⁴; or (b) (C₁-C₃)alkylene or (C₁-C₂)alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;

Cy² is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkyl-alkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocycisulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl; (C₁-C₆)alkylcarbonyl; (C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl, di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminosulfonyl, di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl and di(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

provided that if (a) t is 1; (b) Q is 0, (c) A¹ is CH₂ optionally substituted with R¹ and (d) Cy¹ is phenyl then A²Cy² is not NHR⁴ or optionally substituted heterocyclyl; provided that if (a) A¹ is CH₂CH₂O; (b) Cy¹ is phenyl and (c) A² is CH₂ then Cy² is not heterocyclyl substituted with oxo;

R^(1a) and R^(1b) are each independently selected from (a) hydrogen or (b) (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl which are optionally substituted with up to three groups independently selected from fluorine, hydroxy, (C₁-C₃)alkoxy and H₂NC(═O);

A is straight or branched (C₁-C₆)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl, optionally substituted with up to 4 groups independently selected from fluorine, cyano, oxo, R⁴, —OH R⁴⁰—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴SO₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴⁰S(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, heterocyclylamino (wherein the heterocyclyl portion is optionally substituted by alkyl, haloalkyl or oxo); heteroarylamino (wherein the heteroaryl portion is optionally substituted by alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); arylamino (wherein the aryl portion is optionally substituted by alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and cycloalkylamino (wherein the cycloalkyl portion is optionally substituted by alkyl, haloalkyl or oxo);

t is 1, 2 or 3;

Y is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;

n is 0, 1 or 2;

E is (a) a bond or (b) (C₁-C₃)alkylene or (C₁-C₂)alkylenyloxy, wherein the 0 is attached to R², each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo; provided that if Q is NH, then ER² is not (C₁-C₆)alkyl or benzyl;

R² is (C₁-C₆)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, nitro, hydroxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl-aminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkyl-aminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonyl-amino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkylamino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl; (C₁-C₆)alkylcarbonyl; (C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl, di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminosulfonyl, di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl, {(C₃-C₆)cycloalkyl} {(C_(r) C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl and di(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

wherein the 1 to 4 substituents for the group represented by R² are additionally selected from: amino, cyano, carboxy, (C₁-C₆)alkoxycarbonyl and hydroxy(C₁-C₆)alkyl, when E is bond or (C₁-C₃)alkylene, t is 1 and Q is O or CH₂, provided that ER² is not CH₂Cl, CH₂OH, CHO or CH₂O phenyl; provided that when (a) t is 2; (b) E is bond and (c) R² is phenyl, then R² is not substituted with (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy; provided that when (a) A¹ is bond; (b) R¹ is absent; (c) Cy¹ is phenyl; (d) A² is bond (e) Cy² is H and (f) E is bond, then R² is not unsubstituted phenyl; provided that when (a) t is 1; (b) Q is NR⁵; (c) A¹ is bond; (d) R¹ is absent; (e) Cy¹ is optionally substituted phenyl; (f) A² is bond; (g) Cy² is H then ER² is not unsubstituted (C1-C6) alkyl;

Q is O, NR⁵ or CH₂;

each R⁴ is independently selected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl; and

each R⁵ is independently H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) compound of Formulas I, I₁-I₂₆, Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a method of inhibiting 11β-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, I₁-I₂₆, Ia₁₋₃, Ic₁₋₃, Ic₁₋₃, Ie₁₋₃, If₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a method of treating a subject with a disease associated with the activity or expression of 11β-HSD1, comprising the step of administering to the subject an effective amount of a compound of Formulas I, I₁-I₂₆, Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, If₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is the use of a compound of Formulas I, I₁-I₂₆, Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, If₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for inhibiting 11β-HSD1 activity in a mammal in need of such treatment.

Another embodiment of the invention is the use of a compound of I I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, Id₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for treating a subject with a disease associated with the activity or expression of 11β-HSD1.

Another embodiment of the invention is a compound of Formulas I, I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, Id₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in inhibiting 11β-HSD1 activity in a mammal in need of such treatment.

Another embodiment of the invention is a compound of Formulas I, I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, Id₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in for treating a subject with a disease associated with the activity or expression of 11β-HSD1.

The present invention further provides methods of inhibiting 11β-HSD1 by contacting 11β-HSD1 with a compound of Formula I, I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, If₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ of the invention.

The present invention further provides methods of inhibiting or reducing the conversion of cortisone to cortisol in a cell using a compound of Formula I, I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id_(1-3, Ie) ₁₋₃, If₁₋₃, Ig₁₋₃, Ii₁₋₃ or Ij₁₋₃ of the invention.

The present invention further provides methods of inhibiting or reducing production of cortisol in a cell using a compound of Formula I, I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, If₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ of the invention.

The present invention further provides methods of increasing insulin sensitivity in a subject in need thereof using a compound of Formula I, I₁-I₂₆ Ia₁₋₃, Ib₁₋₃, Ic₁₋₃, Id₁₋₃, Ie₁₋₃, If₁₋₃, Ig₁₋₃, Ih₁₋₃, Ii₁₋₃ or Ij₁₋₃ of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provieds novel compounds that are effective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).

Values and alternative values for the variables in the above-described Structural Formula I are provided herein:

R¹ is (a) absent or (b) is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl, wherein each is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R⁴, R⁴⁰—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—, R⁴⁰S(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino. In another embodiment, R¹ is (C₁-C₆)alkyl. In another embodiment, R¹ is absent or is optionally substituted methyl or ethyl. Alternatively, R¹ is an optionally substituted methyl or ethyl. In yet another embodiment R¹ is unsubstituted.

A¹ is (a) a bond, or (b) (C₁-C₃)alkylene, CH₂CH₂O, wherein the oxygen is attached to Cy¹, or CH₂C(═O), wherein the carbonyl carbon is attached to Cy¹. In another embodiment, A¹ is (C₁-C₃)alkylene. Alternatively, A¹ is (C₂-C₃)alkylene. In another embodiment, A¹ is a bond. In yet another embodiment A¹ is methylene. Alternatively, A¹ is a bond.

Cy¹ is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkox_(Y)(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C_(r) C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl; provided that if (a) t is 2 and Q is O or CH₂ or t is 1 and Q is 0, (b) A¹ is CH₂ optionally substituted with R₁ and (c) A₂ is a bond, then Cy² is meta or para to the ring atom of Cy¹ that is bonded to A¹ and the aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, represented by Cy¹ is not substituted with bromine, iodine, amino, halo(C₁-C₆)alkyl at a ring atom ortho to the carbon atom bounded to A₁. In another embodiment, Cy¹ is optionally substituted aryl or optionally substituted heteroaryl. In another embodiment, Cy¹ is optionally substituted phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy and 2-hydroxy-2-methylpropoxy. In another embodiment, Cy¹ is optionally substituted phenyl or optionally substituted pyridyl. Alternatively, Cy¹ is optionally substituted phenyl. In another embodiment, Cy¹ is phenyl substituted with fluorine, or bromine.

A² is (a) a bond, O, S or NR⁴; or (b) (C₁-C₃)alkylene or (C₁-C₂)alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo. In another embodiment, A² is a bond, O or OCH₂CO. In another embodiment, A² is a bond.

Cy² is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkyl-alkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl; provided that if (a) t is 1; (b) Q is 0, (c) A¹ is CH₂ optionally substituted with R₁ and (d) Cy¹ is phenyl then A₂Cy² is not NHR⁴ and Cy² is not optionally substituted heterocyclyl. In another embodiment, Cy² is optionally substituted aryl or optionally substituted heteroaryl. In another embodiment, Cy² is hydrogen, phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl or piperazinyl optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonyl-aminomethyl or tetrazolyl. In yet another embodiment and Cy² is optionally substituted phenyl or optionally substituted pyridyl. Alternatively, Cy² is optionally substituted phenyl. In another embodiment, Cy² is phenyl substituted with 1 to 4 groups independently selected from chlorine or fluorine. Alternatively, Cy² is difluorophenyl. In another embodiment, Cy² is hydrogen. In another embodiment, Cy² is cyclopropyl.

R^(1a) and R^(1b) are each independently selected from (a) hydrogen or (b) (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl which are optionally substituted with up to three groups independently selected from fluorine, hydroxy, (C₁-C₃)alkoxy and H₂NC(═O). In another embodiment, R^(1a) and R^(1b) are each independently H or (C₁-C₆)alkyl. In yet another embodiment R^(1a) and R^(1b) are each independently H, methyl, or ethyl. In another embodiment, R^(1a) is methyl or ethyl. In yet another embodiment R^(1a) is methyl. In another embodiment, R^(1b) is methyl or hydrogen. Alternatively, R^(1b) is hydrogen.

A is straight or branched (C₁-C₆)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl, optionally substituted with up to 4 groups independently selected from fluorine, cyano, oxo, R⁴, —OH R⁴⁰—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴SO₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, heterocyclylamino (wherein the heterocyclyl portion is optionally substituted by alkyl, haloalkyl or oxo); heteroarylamino (wherein the heteroaryl portion is optionally substituted by alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); arylamino (wherein the aryl portion is optionally substituted by alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and cycloalkylamino (wherein the cycloalkyl portion is optionally substituted by alkyl, haloalkyl or oxo). In another embodiment, A is hydroxy(C₁-C₆)alkyl or (C₁-C₂) alkoxy(C₁-C₆)alkyl. In another embodiment, A is (C₁-C₄)alkylcarbonylamino(C₁-C₄)alkyl. In yet another embodiment, A is mono(C₁-C₂)alkylaminocarbonyl(C₁-C₄)alkyl or di(C₁-C₂)alkylaminocarbonyl(C₁-C₄)alkyl. Alternatively, A is 2-pyrimidinyl-amino(C₁-C₆)alkyl; 2-pyridyl-amino(C₁-C₆)alkyl; mono(C₁-C₂)alkylamino(C₁-C₄)alkyl or di(C₁-C₂)alkylamino(C₁-C₄)alkyl, wherein the pyrimidinyl and pyridyl are each optionally substituted with methyl or ethyl. Alternatively, A is (C₁-C₆)alkyl, optionally substituted with halogen. In another embodiment, A is (C₁-C₄)alkylsulfonyl(C₁-C₄)alkyl. In another embodiment, A is (C₁-C₄)alkylsulfonylamino(C₁-C₄)alkyl. In another embodiment, A is (C₁-C₄)alkoxyalkylamino(C₁-C₄)alkyl. Alternatively, A is mono(C₁-C₄)alkylaminocarbonyl(C₁-C₄)alkyl or di(C₁-C₄)alkylaminocarbonyl(C₁-C₄)alkyl. Alternatively, A is methyl, ethyl, isopropyl or t-butyl. Alternatively, A is methyl or t-butyl.

t is 1, 2 or 3. Alternatively, t is 1 or 2. Alternatively, t is 1. Alternatively, t is 2.

Y is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl.

n is 0, 1 or 2. Alternatively, n is 0.

E is (a) a bond or (b) (C₁-C₃)alkylene or (C₁-C₂)alkylenyloxy, wherein the 0 is attached to R², each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo. Alternatively, E is a bond or (C₁-C₃)alkylene, optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo. Alternatively, E is a bond or CH₂. Alternatively, E is a bond.

R² is (C₁-C₆)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, nitro, hydroxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl-aminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkyl-aminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonyl-amino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl; wherein the 1 to 4 substituents for the group represented by R² are additionally selected from: amino, cyano, carboxy, (C₁-C₆)alkoxycarbonyl and hydroxy(C₁-C₆)alkyl, when E is bond or (C₁-C₃)alkylene, t is 1 and Q is O or CH₂, provided that ER² is not CH₂Cl, CH₂OH, CHO or CH₂O phenyl. In another embodiment, R² is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl. In another embodiment, R² is phenyl, thienyl or pyridyl each optionally substituted with halo or methyl. In another embodiment, R² is optionally substituted phenyl, optionally substituted thienyl or optionally substituted pyridyl. In another embodiment, R² is phenyl or pyridyl optionally substituted with one group selected from halo, methyl, methylthio or (4-morpholino)methyl. In yet another embodiment R² is optionally substituted phenyl or 4-fluorophenyl. In yet another embodiment R² is optionally substituted phenyl. Alternatively, R² is fluorophenyl. In another alternative R² is not alkyl, pyridinyl, cycloalkyl, cycloalkylalkyl, haloalkyl; unsubstituted phenyl, phenyl substituted with one to three substituents independently selected from fluoro, chloro, bromo, haloalkyl, alkoxy, hydroxy, haloalkyl and haloalkoxy, phenylalkyl or pyridinylalkyl, wherein phenylalkyl and pyridinylalkyl are optionally subtituted with one to three substituents independently selected from alkyl, halogen, haloalkyl and hydroxy, oxetane or oxetane substituted with alkyl, phenylalkoxyalkyl or phenylalkoxyalkyl substituted with one to three substituents independently selected from alkyl and halogen, hydroxyalkyl, pyridinyloxyalkyl or pyridinyloxyalkyl substituted with cyano.

Q is O, NR⁵ or CH₂. In another embodiment, Q is CH₂ In another embodiment, Q is O. In yet another embodiment Q is NR⁵.

each R⁴ is independently selected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl; and

each R⁵ is independently H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁:

and wherein values and alternative values for Q, R², E, A, R^(1a), R^(1b), Y, n and t are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂:

and wherein values and alternative values for Q, R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₃:

and wherein values and alternative values for Q, R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₄:

and wherein values and alternative values for Q, R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₅:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₆:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₇:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₈:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₉:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₀:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₁:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₂:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₃:

and wherein values and alternative values for R², E, A, R^(1a), R^(1b), Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₄:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, Cy², Y, n and t are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₅:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₆:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₇:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₈:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₁₉:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₀:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₁:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₂:

and wherein values and alternative values for R², E, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₃:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₄:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₅:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula I₂₆:

and wherein values and alternative values for R², E, A¹, R¹, Cy¹, A², Cy², Y and n are as defined for Formula I above or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ia₁:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, r is 0, 1, 2, 3 or 4 and G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonyl-amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkylamino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl or (C₁-C₆)alkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ia₂:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, G and r are as defined for Formula Ia, above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ia₃:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, G and r are as defined for Formula Ia, above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ib₁:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ib₂:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ib₃:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ic₁:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ic₂:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ic₃:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Id₁:

and wherein values and alternative values for Q, R¹, A¹, Cy¹, A² and Cy² are as defined for Formula I above, m is 0, 1, 2, 3 or 4 and X is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkyl-alkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Id₂:

and wherein values and alternative values for Q, A¹, Cy¹, A² and Cy² are as defined for Formula I above, X and m are as defined for Formula Id₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Id₃:

and wherein values and alternative values for Q, R¹, A¹, Cy¹, A² and Cy² are as defined for Formula I above, X and m are as defined for Formula Id₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ie₁:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, r is 0, 1, 2, 3 or 4 and G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkyl-alkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ie₂:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, G and r are as defined for Formula Ie₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ie₃:

and wherein values and alternative values for Q, R², E, A² and Cy² are as defined for Formula I above, G and r are as defined for Formula Ie, above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula If₁:

and wherein values and alternative values for Q, R² and E are as defined for Formula I above, r and s are independently 0, 1, 2, 3 or 4 and G¹ and G² are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkyl-alkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula If₂:

and wherein values and alternative values for Q, R² and E are as defined for Formula I above, G¹, G², r and s are as defined for Formula If₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula If₃:

and wherein values and alternative values for Q, R² and E are as defined for Formula I above, G¹, G², r and s are as defined for Formula If₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ig₁:

and wherein values and alternative values for Q, R² and E are as defined for Formula I above, r is 0, 1, 2, 3 or 4 and G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkyl-alkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl and (C₁-C₆)alkylcarbonyl, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ig₂:

and wherein values and alternative values for Q, R² and E are as defined for Formula I above, G and r are as defined for Formula Ig₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ig₃:

and wherein values and alternative values for Q, R² and E are as defined for Formula I above, G and r are as defined for Formula Ig₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ih₁:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, A², Cy², Y n and t are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ih₂:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, A², Cy², Y, n and t are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ih₃:

and wherein values and alternative values for Q, R², E, A¹, R¹, Cy¹, A², Cy², Y, n and t are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ii₁:

and wherein values and alternative values for Q, R², E, Y and n are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ii₂:

and wherein values and alternative values for Q, R², E, Y and n are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ii₃:

and wherein values and alternative values for Q, R², E, Y and n are as defined for Formula I above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ij₁:

and wherein values and alternative values for Q, R^(1a), R^(1b) and A are as defined for Formula I above, X and m are as defined for Formula Id₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ij₂:

and wherein values and alternative values for Q, R^(1a), R^(1b) and A are as defined for Formula I above, X and m are as defined for Formula Id₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Structural Formula Ij₃:

and wherein values and alternative values for Q, R^(1a), R^(1b) and A are as defined for Formula I above, X and m are as defined for Formula Id₁ above, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In another embodiment of the invention, values for variables in Structural Formula I or any of Structural Formulas I₁₄-I₂₆ or Ia₁₋₃-Ih₁₋₃ are:

R is

R¹ is absent or is methyl or ethyl; A¹ is a bond or CH₂; Cy¹ is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy and 2-hydroxy-2-methylpropoxy; A² is a bond, O or OCH₂CO; Cy² is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl or piperazinyl optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonyl-aminomethyl or tetrazolyl; n is 0; t is 1, 2 or 3;

Q is O, NR⁵ or CH₂;

E is a bond or CH₂; R² is phenyl or pyridyl optionally substituted with one group selected from halo, methyl, methylthio or (4-morpholino)methyl.

In another embodiment of the invention, values for variable in the Structural

Formula I or any of the formulas I₁-I₁₃ or Ij₁₋₃ are:

R is

R^(1a) is methyl or ethyl; R^(1b) is methyl or hydrogen; A is methyl, ethyl, isopropyl or t-butyl; n is 0; t is 1, 2 or 3;

Q is O, NR⁵ or CH₂;

E is a bond or CH₂; and R² is phenyl, thienyl or pyridyl each optionally substituted with halo or methyl.

Definitions

The term “alkyl” means a straight or branched hydrocarbon radical having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “cycloalkyl” means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, Spiro[4.4]nonane, adamantyl and the like.

The term “aryl” means an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group. An aryl group is optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.

The term “heteroaryl” means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or 5-imidazolyl. A heteroaryl is optionally substituted. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.

The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. Exemplary heterocyclyls include pyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4-pyridone, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, piperazin-2-one, 5,6-dihydropyrimidin-4-one, pyrimidin-4-one, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide and isothiazolidine 1,1-dioxide. A heterocyclyl can be optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, haloalkyl and oxo.

As used herein the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included. “Solvates” refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

Certain of the disclosed comopounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a chiral carbon center. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R” and “S” denote the relative configurations of substituents around one or more chiral carbon atoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.

“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.

The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical isomer, a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).

The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

The following abbreviations have the indicated meanings:

Abbreviation Meaning Boc tert-butoxy carbonyl or t-butoxy carbonyl (Boc)₂O di-tert-butyl dicarbonate Cbz Benzyloxycarbonyl CbzCl Benzyl chloroformate DAST diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N′-dicyclohexylcarbodiimide DCU N,N′-dicyclohexylurea DIAD diisopropyl azodicarboxylate DIEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2,4-DNP 2,4-dinitrophenylhydrazine DPTBS Diphenyl-t-butylsilyl EDC.HCl, EDCl 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride Equiv equivalents EtOAc ethyl acetate Fmoc 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- Fmoc-OSu 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedione h, hr hour(s) HOBt 1-hydroxybenzotriazole HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3, 3-tetramethyluronium hexafluorophosphate HBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate KHMDS potassium hexamethyldisilazane LAH or LiAlH₄ lithium aluminum hydride LC-MS liquid chromatography-mass spectroscopy LHMDS lithium hexamethyldisilazane m-CPBA 3-chloroperoxybenzoic acid Me methyl MsCl methanesulfonyl chloride Min minute MS mass spectrum NaH sodium hydride NaHCO₃ sodium bicarbonate NaN₃ sodium azide NaOH sodium hydroxide Na₂SO₄ sodium sulfate NMM N-methylmorpholine NMP N-methylpyrrolidinone Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether Quant quantitative yield rt room temperature Satd saturated SOCl₂ thionyl chloride SFC supercritical fluid chromatography SPA scintillation proximity assay SPE solid phase extraction TBAF tetrabutylammonium fluoride TBS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TBSCl t-butyldimethylsilyl chloride TBDPSCl t-butyldiphenylsilyl chloride TEA triethylamine or Et₃N TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical Teoc 1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin- 2,5-dione TFA trifluoroacetic acid Tlc, TLC thin layer chromatography TMS trimethylsilyl TMSCl chlorotrimethylsilane or trimethylsilyl chloride t_(R) retention time TsOH p-toluenesulfonic acid

General Description of Synthetic Methods

Compounds of Formula I can be prepared by several processes. In the discussion below, A, A¹, A², Cy¹, E, R¹, R², R⁵, R^(1a), R^(1b), Y, n and t have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products of Formulas I described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not described explicitly. Generally, reagents in the reaction schemes are used in equimolar amounts; however, in certain cases it may be desirable to use an excess of one reagent to drive a reaction to completion.

This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCl in reaction mixtures are generally used in slight to substantial excess (1.05-5 equivalents).

In a first process compounds of Formula I, wherein t is 2, n is 0 and Q is CH₂, are prepared by ring closure of intermediates of Formula II wherein Z^(a) is a leaving group such as halide, alkanesulfonate, haloalkanesulfonate or arylsulfonate, using a base such as NaH.

Intermediates of Formula II, wherein Z^(a) is alkanesulfonate, haloalkanesulfonate or arylsulfonate, can be prepared from alchols of Formula III and sulfonyl chlorides of Formula IV (Z^(a)═Cl) or sulfonic anhydrides of Formula IV (Z^(a)═R^(a)SO₂O—), wherein R^(a) is alkyl, haloalkyl or aryl.

Alcohols of Formula III can be prepared by reduction of carboxylic acids of Formula V using, for example, borane in THF.

Carboxylic acids of Formula V can be prepared by reaction of cyclic anhydrides of Formula VI with amines of Formula VII.

Cyclic anhydrides of Formula VI can be prepared from diacids of Formula VIII by treatment with acetic or trifluoroacetic anhydride.

Diacids of Formula VIII can be prepared from aldehydes of Formula IX and β-ketoesters of Formula X, wherein R^(b) is lower alkyl, by reaction with piperidine under Knoevenagel conditions, followed by treatment with NaOH and with HCl.

Amine intermediates of Formula VII, wherein A¹=CH₂ and R¹ is absent, can be prepared by reduction of amides of Formula XI using a hydride reagent such as BH₃.THF solution, BH₃.Me₂S or LiAlH₄ in an ethereal solvent such as THF or DME at 20° C. to 100° C. for between 1 h and 48 h:

Amine intermediates of Formula VII, wherein A¹ is a bond, R¹ is absent and Cy¹ is not an aromatic or heteroaromatic ring, can be prepared from ketones of formula XII via oximes of Formula XIII or by reductive amination of ketones of Formula XII with ammonia:

Methods for the conversion of ketones to oximes are described in Smith, M. B. and March, J. “March's Advanced Organic Chemistry” pp 1194-1195, 5^(th) Edition, Wiley, New York, N.Y., 2001. Methods for the reduction of oximes to primary amines are described in Smith, M. B. and March, J. “March's Advanced Organic Chemistry” p 1555, 5^(th)) Edition, Wiley, New York, N.Y., 2001. Methods for the reductive amination of ketones are described in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

Amine intermediates of Formula VII, wherein A¹ is CH, can be prepared from ketones of Formula XIV by reductive amination with ammonia.

Amine intermediates of Formula VII, wherein A¹ is CH, can be prepared from alcohols of Formula XV via azides of Formula XVI. The conversion of alcohols of Formula XV to azides of Formula XVI can be accomplished with, for example, diphenylphosphoryl azide. Reduction of azides of Formula XVI to amines of Formula VII can be effected, for example, by hydrogenation in the presence of a palladium catalyst or by reaction with triphenylphosphine in wet THF.

Amine intermediates of Formula VII, wherein A¹ is CH, can be prepared by reaction of sulfinyl imine intermediates of Formula XVII with organometallic reagents of Formula XVIII, wherein M is Li, MgCl, MgBr or MgI, followed by treatment with acid to remove the t-butylsulfinyl group.

Sulfinyl imines of Formula XVII can be prepared by treatment of aldehyde intermediates of Formula XVIII with 2-methylpropane-2-sulfinamide.

In a second process, compounds of Formula I, wherein Q is O or NR⁵, can be prepared by reaction of aminoalcohols or diamines intermediate of Formula XIX with reagents of Formula XX, wherein Z¹ and Z² are leaving groups such as chloride, 1-imidazolyl or aryloxide in an inert solvent such as THF, CH₂Cl₂, toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO₃ respectively, at −10° C. to 120° C.:

Certain instances of reagent XX are especially convenient because they are commercially available. For example when Z¹ and Z² are both chloride, XX is phosgene. When Z¹ and Z² are both 1-imidazolyl, XX is carbonyl diimidazole. When Z¹ is chloride and Z² is p-nitrophenoxide, XX is p-nitrophenyl chloroformate. When Z¹ and Z² are both OCCl₃, XX is triphosgene and as little as one third of molar equivalent can be used.

Aminoalcohol and diamine intermediates of Formula XIX, wherein n=0, can be prepared by reduction of amides of Formula XXI using a hydride reagent such as BH₃.THF solution, BH₃.Me₂S or LiAlH₄ in an ethereal solvent such as THF or DME at 20° C. to 100° C. for between 1 h and 48 h:

Intermediates of Formula XXI can be prepared by coupling of α-, β- or γ-hydroxyacids (Q=0) and α-, β- or γ-aminoacids (Q=NR⁵) of Formula XXII with amines of Formula VII using standard peptide coupling reagents such as EDC in the presence of HOBt and N,N-diisopropylethylamine in an inert solvent such as CH₂Cl₂ at 0-30° C. for between 1 h and 24 h:

In a third process, compounds of Formula I, wherein Q is 0 and t is 1 or 2, can be prepared by reaction of hydroxycarbamates of Formula XXIII, wherein R^(c) is an alkyl or arylalkyl group such as methyl, t-butyl or benzyl, with a strong base such as NaH.

Hydroxycarbamates of Formula XXIII can be prepared by reduction of ketocarbamates of Formula XXIV with, for example, NaBH₄ in MeOH.

Ketocarbamates of Formula XXIV can be prepared by reaction of β-aminoketonesof Formula XXV with reagents of Formula XXVI, wherein R^(d) is a leaving group such as chloride, succinyloxy, imidazolyl or t-butoxycarboxycarbonyl:

β-Aminoketones of Formula XXV, wherein n=0 and t is 2, can be prepared by reaction of α,β-unsaturated ketones of Formula XXVII or β-chloroketones of Formula XXVIII with amines of Formula VII:

α-Aminoketones of Formula XXV, wherein n=0 and t is 1, can be prepared by reaction of α-haloketones of Formula XXIX, wherein Z³ is Br or Cl, with amines of Formula VII:

Hydroxycarbamates of Formula XXIII can also be prepared by addition of organometallic reagents of Formula XXX, wherein M is Li, MgCl, MgBr or MgI, to aldehydes of Formula XXXI.

Aldehydes of Formula XXXI can be prepared by oxidation of alcohols of Formula XXXII with, for example, Dess-Martin periodinane. Alcohols of Formula XXXII can be prepared by reduction of esters of Formula XXXIII, wherein R^(d) is alkyl or arylalkyl using for example LiAlH₄, or by reduction of acids of Formula XXXI, wherein R^(d) is hydrogen, using for example isobutyl chloroformate and NaBH₄.

Esters of Formula Formula XXXIII, wherein n is 0 and t is 1, can be prepared by alkylation of carbamates of Formula XXXIV with bromoacetic acid esters of Formula XXXV using a base such as NaH.

In a fourth process compounds of Formula I, wherein Q is 0 and t is 1 or 2, can be prepared by reaction of alcohols of Formula XXXVI, wherein Z⁴ is halide, alkanesulfonate, haloalkanesulfonate or arylsulfonate, with isocyanates of Formula XXXVII in the presence of a base:

Isocyanates of Formula XXXVII can be prepared from amines of Formula VII by treatment with phosgene, diphosgene or triphosgene.

Alcohols of Formula XXXVI, wherein Z⁴ is chloride and t is 2, can be prepared by reduction of β-haloketones of Formula XXVIII with hydride reagents such as NaBH₄. Similarly, alcohols of Formula XXXVI, wherein Z⁴ is chloride or bromide and t is 1, can be prepared by reduction of α-haloketones of Formula XXIX, wherein Z³ is chloride or bromide using a hydride reagent such as NaBH₄.

In a fifth process compounds of Formula I, wherein A¹ is CH₂ and R¹ is absent, can be prepared by reaction of compounds of Formula XXXVII, with alkylating agents of Formula XXXVIII, wherein Z⁵ is a leaving group such as Br, I, OSO₂Me, OSO₂CF₃ or OSO₂Ph, in the presence of a base such as NaH or K₂CO₃:

Compounds of Formula XXXVII, wherein Q=O or NR⁵, can be prepared by treatment of compounds of Formula XXXIX with various reagents of Formula XX, wherein Z¹ and Z² are leaving groups such as chloride, 1-imidazolyl or aryloxide in an inert solvent such as THF, CH₂Cl₂, toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO₃ respectively, at −10° C. to 120° C.:

Compounds of Formula XXXVII, wherein Q is CH₂, can be prepared by ring expansion of ketones of Formula XL with hydrazoic acid under Schmidt reaction conditions.

In a sixth process compounds of Formula I, wherein A is a bond can be prepared by reaction of compounds of Formula XXXVII, with compounds of Formula XLI, wherein Z⁶ is a leaving group such as chloro, bromo, iodo or OSO₂CF₃, in the presence of a base such as K₂CO₃ and a copper or palladium catalyst in an inert solvent such as dioxane, DMF or NMP at elevated temperature:

In a seventh process, compounds of Formula I, wherein Q is CH₂ and A¹ is CH₂ and R¹ is absent, can be prepared by reaction of ketones of Formula XL with azides of Formula XLII in the presence of TiCl₄.

In an eighth process, compounds of Formula I, wherein Q is CH₂, are prepared by photolytic rearrangement of oxaziridines of Formula XLIII.

Oxaziridines of Formula XLIII can be prepared from ketones of Formula XL and amines of Formula VII to form imines of Formula XLIV, followed by oxidation with, for example, m-CPBA.

In a ninth process, compounds of Formula I can be prepared from other compounds of Formula I. For example:

(1) a compound of Formula I wherein Cy¹ is substituted with bromine or iodine, A² is a bond and Cy² is hydrogen can be reacted with an optionally substituted aryl or heteroarylboronic acid or ester in the presence of a palladium catalyst to give a compound of Formula I wherein A² is a bond and Cy² is optionally substituted aryl or heteroaryl.

(2) a compound of Formula I wherein R¹ is ω-hydroxy(C₂-C₆)alkyl can be oxidized to a compound of Formula I wherein R¹ is ω-carboxy(C₁-C₆)alkyl using Jones reagent.

(3) a compound of Formula I wherein R¹ is ω-carboxy(C₁-C₆)alkyl can be coupled with ammonia or a (C₁-C₆)alkylamine using a standard peptide coupling reagent such as EDC to afford a compound of Formula I wherein R¹ is ω-H₂NC(═O)(C₁-C₆)alkyl or ω-{(C₁-C₆)alkylNHC(═O)}(C₁-C₆)alkyl.

(4) a compound of Formula I wherein R¹ is ω-hydroxy(C₁-C₆)alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with sodium azide and reduced to give a compound of Formula I, wherein R¹ is ω-amino(C₁-C₆)alkyl.

(5) a compound of Formula I wherein R¹ is amino(C₁-C₆)alkyl can be reacted with acetic anhydride or acetyl chloride to give a compound of Formula I wherein R¹ is {acetylamino}(C₁-C₆)alkyl.

(6) a compound of Formula I wherein R¹ is amino(C₁-C₆)alkyl can be reacted with methanesulfonyl chloride to give a compound of Formula I wherein R¹ is {methanesulfonylamino}(C₁-C₆)alkyl.

(7) a compound of Formula I, wherein R¹ is (C₂-C₆)alkenyl, is hydroborated to afford a compound of Formula I wherein is hydroxy(C₂-C₆)alkyl,

(8) a compound of Formula I, wherein R¹ is (C₂-C₆)alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a compound of Formula I wherein Fe is vicinal dihydroxy(C₂-C₆)alkyl,

(9) a compound of Formula I, wherein R¹ is H₂C═CH(C_(o)-C₄)alkyl-, can be reacted with ozone followed by NaBH₄ to give a compound of Formula I wherein R¹ is ω-hydroxy(C₁-C₆)alkyl.

(10) a compound of Formula I wherein R¹ is amino(C₁-C₆)alkyl can be reacted with an (C₁-C₆)alkyl isocyanate to give a compound of Formula I wherein R¹ is (C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl.

(11) a compound of Formula I wherein R¹ is amino(C₁-C₆)alkyl can be reacted with an (C₁-C₆)alkyl chloroformate to give a compound of Formula I wherein is (C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl.

(12) a compound of Formula I wherein R¹ is amino(C₁-C₆)alkyl can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I wherein R¹ is aminosulfonylamino(C₁-C₆)alkyl.

(13) a compound of Formula I wherein R¹ is amino(C₁-C₆)alkyl can be reacted with a (C₁-C₆)alkylsulfamoyl chloride to give a compound of Formula I wherein R¹ is (C₁-C₆)alkylaminosulfonylamino(C₁-C₆)alkyl.

(14) a compound of Formula I wherein R¹ is hydroxy(C₁-C₆)alkyl can be reacted with chlorosulfonyl isocyanate to give a compound of Formula I wherein R¹ is aminosulfonyloxy(C₁-C₆)alkyl.

(15) a compound of Formula I wherein R¹ is hydroxy(C₁-C₆)alkyl can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (C₁-C₆)alkylamine or a di(C₁-C₆)alkylamine to give a compound of Formula I wherein R¹ is aminocarboxy(C₁-C₆)alkyl, (C₁-C₆)alkyl aminocarboxy(C₁-C₆)alkyl or di(C₁-C₆)alkyl aminocarboxy(C₁-C₆)alkyl.

(16) a compound of Formula I wherein R¹ is hydroxy(C₁-C₆)alkyl can be reacted with POCl₃ to give a compound of Formula I wherein R′ is (HO)₂P(═O)O(C₁-C₆)alkyl.

(17) a compound of Formula I wherein Cy¹ is substituted with bromine or iodine, A² is a bond and Cy² is hydrogen can be reacted with a cyclic amine in the presence of a palladium catalyst to give a compound of Formula I wherein A² is a bond and Cy² is a cyclic amino moiety attached through its nitrogen atom.

(18) a compound of Formula I wherein Q is NR⁵ and R⁵ is H can be reacted with an (C₁-C₆)alkyl halide in the presence of a strong base such as sodium hydride to afford a compound of Formula I wherein Q is NR⁵ and R⁵ is (C₁-C₆)alkyl.

(19) a compound of Formula I wherein R¹ ω-H₂NCO(C₁-C₅)alkyl can be reacted with TFAA in the presence of pyridine to afford a compound of Formula I wherein R¹ is ω-cyano(C₁-C₅)alkyl.

(20) a compound of Formula I, wherein R¹ is ω-MeO₂C(C₁-C₅)alkyl can be reacted with at least 2 equivalents of MeMgBr to afford a compound of Formula I, wherein R¹ or HOC(Me)₂(C₁-C₅)alkyl.

(21) a compound of Formula I wherein R¹ is ω-hydroxy(C₁-C₆)alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate and reacted with morpholine to give a compound of Formula I, wherein R¹ is ω-(4-morpholino)(C₁-C₆)alkyl.

The synthetic methods described above are generally applicable when R is

Purification Methods

Compounds of the invention can be purified by high pressure liquid chromatography (prep HPLC). Unless otherwise specified, prep HPLC refers to preparative reverse phase HPLC on a C-18 column eluted with a water/acetonitrile gradient containing 0.01% TFA run on a Gilson 215 system.

LC-MS Methods

Method 1 [LC-MS (3 min)] Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01% TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10

Method 2 (10-80)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA (1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B % 0   90 10 2.2 20 80 2.5 20 80 Flow Rate 1 mL/min Wavelength UV 220 nm Oven Temp 50° C. MS ESI ionization

Example 1 (S)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one

Step 1

To a solution of (S)-1-phenylpropane-1,3-diol (500 mg, 3.28 mmol) and triethylamine (399 mg, 3.94 mmol) in CH₂Cl₂ (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (626 mg, 3.28 mol) slowly at 0° C., and the reaction mixture was stirred at rt for 2 h. The reaction solution was dried over Na₂SO₄ and concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (576 mg, 57%). ¹H NMR (400 MHz, CDCl₃): δ=1.91-2.00 (m, 3H), 2.48 (s, 2H), 4.00 (m; 1H), 4.22 (m, 1H), 4.75 (m, 2H), 7.25-7.30 (m, 7H), 7.75 (d, 2H).

Step 2

To a solution of the (S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (100 mg, 0.33 mmol) in anhydrous acetonitrile (2 mL) were added K₂CO₃ (91 mg, 0.66 mmol), NaI (12 mg, 0.0825 mmol) and m-toluidine (42 mg, 0.39 mmol). The mixture was refluxed overnight. The mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-3-(m-tolylamino)-1-phenylpropan-1-ol (45 mg, 57%). ¹H NMR (400 MHz, CDCl₃): δ=2.05 (m, 2H), 2.25 (s, 3H), 3.25 (m, 2H), 3.40 (s, 2H), 4.90 (m, 1H), 6.50 (m, 4H), 7.05 (m, 1H), 7.30 (m, 1H), 7.40 (d, 3H).

Step 3

To a solution of (S)-3-(m-tolylamino)-1-phenylpropan-1-ol (40 mg, 0.17 mmol) in dry CH₂Cl₂ (1 mL) was added triethylamine (50 mg, 0.51 mmol) and bis(trichloromethyl) carbonate (20 mg, 0.067 mmol) at 0° C., and the reaction mixture was stirred overnight at room temperature. When the reaction was over, the mixture was concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (12 mg, 26%). ¹H NMR: (400 MHz, CDCl₃): δ=2.24-2.37 (m, 5H), 3.52-3.63 (m, 1H), 3.70-3.79 (m, 1H), 5.42 (dd, 1H), 7.01-7.10 (m, 3H), 7.18-7.23 (m, 2H), 7.32-7.39 (m, 4H).

Example 2 (R)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one

To a solution of (R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (100 mg, 0.327 mmol) and 1-isocyanato-3-methylbenzene (44 mg, 0.327 mmol) in CH₂Cl₂ (2 mL) was added DBU (149 mg, 0.981 mmol) and the reaction mixture was refluxed overnight. After the solvent was removed under reduced pressure, the residue was separated by preparative HPLC to give (R)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (5.34 mg, 6%:). LC-MS (10-80) t_(R)=2.439 min, m/z=268; ¹H NMR (CDCl₃): 2.30-2.34 (m, 5H), 3.63-3.68 (m, 1H), 3.80-3.86 (m, 1H), 5.49 (dd, 1H), 7.09-7.45 (m, 9H).

Example 3 (R)-3-(naphthalen-1-yl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 2 using (R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and 1-isocyanatonaphthalene. LC-MS (10-80) t_(R)=2.625 min, m/z=304; ¹H NMR (CDCl₃) δ 2.44-2.55 (m, 3H), 3.64-3.69 (m, 1H), 3.84-3.91 (m, 1H), 5.62-5.72 (m, 1H), 7.38-7.61 (m, 9H), 7.86-7.93 (m, 3H).

Example 4 3-(3-bromophenyl)-6-(2-chlorophenyl)-1,3-oxazinan-2-one

Step 1

At 0° C., concentrated HCl was added dropwise to Me₂NH (40% in water, 5.57 mL, 1.1 equiv) to acidify the amine. After the addition, 1-(2-chlorophenyl)ethanone (6.18 g, 0.04 mol) and paraformaldehyde (1.68 g, 1.4 equiv) were added. The mixture was dissolved in ethanol (20 mL) and heated to reflux for 30 h. LC-MS found the starting material was gone. The reaction mixture was cooled to rt. The volatiles were removed in vacuo. EtOAc (30 mL) was added and the suspension was stirred for 15 min. The solid was collected by filtration and washed with EtOAc (2×5 mL). The white solid was dried under vacuum to afford 1-(2-chlorophenyl)-3-(dimethylamino)propan-1-one HCl salt (5.17 g, 61% yield). LC-MS (3 min) t_(R)=0.72 min, m/z 212, 214(M+1).

Step 2

A solution of 1-(2-chlorophenyl)-3-(dimethylamino)propan-1-one HCl salt (5.17 g, 20.85 mmol) and 3-bromoaniline (2.27 mL, 1 equiv) in 1:1 ethanol/water (21 mL, 1.0M) was heated at reflux overnight. LC-MS found the starting material was gone. The reaction mixture was cooled to rt. The ethanol was removed in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with 1% aq HCl (2×30 mL), satd aq NaHCO₃ solution (20 mL), brine (20 mL), and dried over Na₂SO₄. After filtration and concentration, the residue (6.08 g) was purified by chromatography on a 120-g silica cartridge to afford 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (2.75 g, 40% yield) as an orange oil. LC-MS (3 min) t_(R)=2.03 min, m/z=340, 341(M+1); ¹H NMR (CDCl₃) δ 7.47(d, 1H), 7.44-7.38 (m, 2H), 7.33 (td, 1H), 7.00 (m, 1H), 6.84 (m, 1H), 6.77 (s, 1H), 6.56 (m, 1H).

Step 3

A solution of 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (50 mg, 0.148 mmol) in 4:1 THF/methanol (5 mL) was cooled to 0° C. NaBH₄ (11 mg, 2 equiv) was added. After 10 min, the mixture was warmed up to rt slowly and stirred for 2 h. The mixture was concentrated, diluted with EtOAc (7 mL), washed with 1% aq HCl (1 mL), and dried over Na₂SO₄. Filtration and concentration afforded crude 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-ol which was used without further purification. LC-MS (3 min) t_(R)=1.93 min, m/z=342,343(M+1).

Step 4

Half of the crude 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-ol (0.074 mmol) was mixed with triphosgene (7.5 mg, 0.34 equiv), i-Pr₂NEt (26 μL, 2 equiv), pyridine (30 μL, 5 equiv) and acetonitrile (5 mL). The mixture was put in the microwave oven for 30 min at 110° C. LC-MS found the reaction completed. The mixture was concentrated, redissolved in EtOAc (5 mL), washed with 1% aq HCl (2×2 mL), concentrated and purified by preparative HPLC to afford 3-(3-bromo-phenyl)-6-(2-chloro-phenyl)-[1,3]oxazinan-2-one (15.2 mg). LC-MS (3 min) t_(R)=1.86 min., m/z 368,369(M+1). ¹H NMR (CDCl₃) δ 7.63(d, 1H), 7.56 (s, 1H), 7.43-7.26 (m, 6H), 5.83 (d, 1H), 3.88 (q, 1H), 3.67 (m, 1H), 2.55 (d, 1H), 2.17 (m, 1H).

Example 5 1-((1S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-phenylpiperidin-2-one

Step 1

3-Phenylglutaric anhydride (1.0 g, 5.26 mmol, 1.0 equiv) was dissolved in toluene (42 mL) and the solution cooled to −78° C. under an N₂ atmosphere. In a separate flask triethylamine (0.75 mL, 542 mg, 5.35 mmol, 1.05 equiv) and (R)-1-(4-bromophenyl)ethanamine (1163 mg, 5.79 mmol, 1.25 equiv) were dissolved in 21 mL of toluene and this solution added drop-wise via syringe over a 0.5 h period and the resulting solution was allowed to stir overnight while warming to rt. After this time 1.0 M aq HCl (−50 mL) was added and the mixture was transferred to a separatory funnel. The layers were separated and the organic layer washed with brine, dried over Na₂SO₄, filtered and evaporated. The resulting 5-((S)-1-(4-bromophenyl)ethylamino)-5-oxo-3-phenylpentanoic acid (1.92 g, 93%) was of sufficient purity to use in the next step.

Step 2

5-((S)-1-(4-bromophenyl)ethylamino)-5-oxo-3-phenylpentanoic acid (1.92 g, 4.92 mmol, 1.0 equiv) was dissolved in THF (30 mL) and the resulting solution cooled to 0° C. Borane (1.0 M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv) was added via syringe. After 0.5 h LC-MS showed formation of the alcohol. The excess borane was quenched by the drop-wise addition of 1.0 M aq HCl and the mixture was transferred to a separatory funnel. The layers were separated and the organic layer washed with brine, dried over Na₂SO₄, filtered and evaporated. The resulting N—((S)-1-(4-bromophenyl)ethyl)-5-hydroxy-3-phenylpentanamide (˜1.9 g, >95% yield) was of sufficient purity to use in the next step.

Step 3

N—((S)-1-(4-bromophenyl)ethyl)-5-hydroxy-3-phenylpentanamide (˜1.9 g, 5 mmol, 1.0 equiv) was dissolved in CH₂Cl₂ (30 mL) and cooled to 0° C. Methanesulfonyl chloride (1.15 g, 10 mmol, 2.0 equiv) and triethylamine (2.1 g, 20 mmol, 4.0 equiv) were added sequentially and the resulting mixture stirred for 1 h. After this time LC-MS analysis showed consumption of the starting alcohol. The mixture was transferred to a separatory funnel and the organic layer was washed with 0.1 M aq HCl and brine, dried over Na₂SO₄, filtered and evaporated. The mesylate was purified by flash chromatography on silica, eluting with 0-47% EtOAc in hexanes. This provided 5-((S)-1-(4-bromophenyl)ethylamino)-5-oxo-3-phenylpentyl methanesulfonate (834 mg, 37%).

Step 4

Sodium hydride (60% in oil, 294 mg, 7.4 mmol, 4.0 equiv) was slurried in DMF (10 mL) and cooled to 0° C. 5-((S)-1-(4-bromophenyl)ethylamino)-5-oxo-3-phenylpentyl methanesulfonate (834 mg, 1.8 mmol, 1.0 equiv) was dissolved in DMF (5 mL) and the solution added via syringe to the NaH slurry. The flask was rinsed with DMF and the mixture was stirred for 2 h. After this time the mesylate was consumed. The DMF was removed and the residue was taken up in EtOAc/H₂O.

The layers were separated and the organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated. The lactam was purified by flash chromatography to provide 1-((S)-1-(4-bromophenyl)ethyl)-4-phenylpiperidin-2-one (291 mg, 81%).

Step 5

1-((S)-1-(4-bromophenyl)ethyl)-4-phenylpiperidin-2-one (291 mg, 0.813 mmol, 1.0 equiv), PdCl₂(dppf) (17 mg, 0.020 mmol, 2.5 mol %), Cs₂CO₃ (530 mg, 1.63 mmol. 2.0 equiv), and 2,4-difluorophenylboronic acid (194 mg, 1.72 mmol, 1.5 equiv) were added to a flask which was evacuated and back-filled with nitrogen, This was repeated twice. Dioxane (20 mL) was added and the red mixture heated to 70° C. under nitrogen for 17 h. After this time LC-MS showed formation of the biaryl. The mixture diluted with EtOAc/H₂O and transferred to a separatory funnel. The organic layer washed with brine, dried over Na₂SO₄, filtered and evaporated. The biaryl was purified by flash chromatography. A small portion was purified by prep HPLC to provide the above biaryl-lactam as a mixture of epimers. LC-MS (3 min): t_(R)=2.13 min, m/z=392. ¹H NMR (CD₃OD): δ 7.54-7.42 (m, 5H), 7.32-7.20 (m, 5H), 7.07-7.02 (m, 2H), 6.08 (q, J=7.0 Hz, 1H), 3.28 (m, 1H), 3.07 (m, 1H), 2.89 (m, 1H), 2.75 (m, 1H), 2.58 (m, 1H), 2.0 (m, 2H), 1.56 (d, J=7 Hz, 3H) ppm. The methyl group of the minor diastereomer, ˜10%, is observed at 1.61 ppm with a similar coupling constant.

¹⁹F NMR (CD₃OD): δ −113.8 (“sept”), −115,8 (“q”).

Example 6 4(-4-fluorophenyl)-1-((1S)-1-(4-methoxylphenyl)ethyl)piperidin-2-one

The title compound was prepared following procedures analogous to those described in Example 5 Step 1-4 using 3-(4-fluorophenylglutaric anhydride and (S)-1-(4-methoxyphenyl)ethanamine in Step 1. LC-MS (3 min): t_(R)=1.79 min, m/z=350. ¹H NMR (CD₃OD): 7.25 (m, 4H), 7.01 (m, 2H), 6.90 (m, 2), 5.99 (bt, 1H), 3.76 (s, 3H), 3.1-2.2 (m, 2H), 2.74 (m, 1H), 2.54 (m, 2H), 1.98-1.82 (m, 2H), 1.53 and 1.48 (d, J=7 Hz, 3H). The two diastereomers are observed in ˜2:1 ratio. ¹⁹F NMR (CD₃OD): δ −119.

Example 7 3-((1S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

Step 1

To a stirred solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (789 mg, 4.23 mmol) and i-Pr₂NEt (0.91 mL, 5.1 mmol) in THF (10 mL) was added (S)-1-(4-bromophenyl)ethanamine (0.68 mL, 4.65 mmol). The mixture was stirred overnight at rt and 10% aq K₂CO₃ (10 mL) and di-tert-butyl dicarbonate (1.38 g, 6.35 mmol) were added. The mixture was stirred overnight at rt and concentrated under reduced pressure. The aqueous residue was extracted with ether (100 mL). The ether extract was washed with 5% aq HCl (20 mL), satd aq NaHCO₃ (20 mL) and brine (20 mL), and dried over Na₂SO₄. Removal of the solvent left an oil (3.77 g) which was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-60% EtOAc in hexanes gradient to afford (5)-tert-butyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (2.04 g, quant) as a waxy solid. LC-MS (3 min) t_(R)=2.35 min, m/z=474, 472, 452, 450, 352, 350.

Step 2

To a stirred solution of (S)-tert-butyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (500 mg, 1.11 mmol) in MeOH (20 mL) was added an NaBH₄ caplet (1 g, 26 mmol). The mixture was stirred at rt overnight and concentrated under reduced pressure. The residue was partitioned between EtOAc (80 mL) and water (20 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to leave tert-butyl (S)-1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-hydroxypropyl)carbamate (474 mg, 94%) as an oil. LC-MS (3 min) t_(R)=2.33 min, 454. 452, 380, 378.

Step 3

To a stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-hydroxypropyl)carbamate (474 mg, 1.05 mmol) in dry THF (10 mL) was added 60% NaH in oil (250 mg, 10.4 mmol). The mixture was heated at reflux for 3 h. The mixture was diluted with water (20 mL) and. EtOAc (80 mL). The organic layer was separated, washed with 5% aq HCl (20 mL), satd aq NaHCO₃ (20 mL) and brine (20 mL), and dried over Na₂SO₄. Removal of the solvent left an oil (348 mg). A portion of the crude product was purified by preparative HPLC to afford 3-((1S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one as a 2:1 mixture of diastereomers based on ¹H NMR. LC-MS (3 min) t_(R)=1.92 min, m/z=380, 378. ¹H NMR (CDCl₃) S [selected resonances of major and minor diastereomers] 1.52 (d, major), 1.59 (d, minor), 3.06 (m, major), 3.31 (m, minor), 5.20 (dd, major), 5.25 (dd, minor).

Example 8 1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one

Step 1

To a stirred solution of benzoylpropionic acid (2.00 g, 11.2 mmol), (S)-1-(4-bromophenyl)ethanamine (2.25 g, 11.2 mmol), HOBt (1.72 g, 11.2 mmol) and i-Pr₂NEt (2.2 mL, 12.3 mmol) in CH₂Cl₂ (40 mL) was added EDC.HCl (2.37 g, 12.3 mmol). The mixture was stirred at rt for 4 h and diluted with EtOAc (140 mL) and 5% aq HCl (50 mL). The mixture was filtered and (S)—N-(1-(4-bromophenyl)ethyl)-4-oxo-4-phenylbutanamide (3.80 g, 93%) was collected as a white solid. ¹H NMR (d₆-DMSO) δ 1.28 (d, 3H), 2.50 (m, 2H), 3.19 (m, 2H), 4.82 (m, 1H), 7.23 (d, 2H), 7.47 (4H), 7.59 (m, 1H), 7.92 (d, 2H), 8.38 (d, 1H).

Step 2

A 250-mL RBF equipped with a magnetic stirbar was charged with solid (S)—N-(1-(4-bromophenyl)ethyl)-4-oxo-4-phenylbutanamide (2.85 g, 7.9 mmol) and placed in an ice bath. To the stirred solid was added 1.0 M BH₃ in THF (30 mL, 30 mmol). The ice bath was removed and the mixture was stirred at rt for 2.5 h. The mixture was poured into 5% aq HCl (100 mL) and concentrated under reduced pressure to remove the THF. The aqueous residue was basified to pH 14 by portionwise addition of NaOH pellets. The mixture was extracted with CH₂Cl₂ (2×100 mL). The combined CH₂Cl₂ extracts were dried over Na₂SO₄. Removal of the solvent afforded crude 4-((S)-1-(4-bromophenyl)ethylamino)-1-phenylbutan-1-ol (2.58° g, 94%) as an oil. LC-MS Method 1 t_(R)=1.20 min, m/z=348, 350.

Step 3

To a stirred solution of crude 4-((S)-1-(4-bromophenyl)ethylamino)-1-phenylbutan-1-ol (2.46 g, 7.1 mmol) in THF (40 mL) was added 10% aq K₂CO₃ (40 mL), followed by di-t-butyl dicarbonate (1.90 g, 8.5 mmol). The mixture was stirred overnight at rt and concentrated to remove THF. The aqueous residue was extracted with EtOAc (2×80 mL). The combined EtOAc extracts were washed with brine (40 mL) and dried over MgSO₄. Removal of the solvent left tert-butyl (S)-1-(4-bromophenyl)ethyl(4-hydroxy-4-phenylbutyl)carbamate (3.24 g, quant). LC-MS Method 1 t_(R)=1.20 min, m/z=472, 470, 350, 348.

Step 4

To a stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(4-hydroxy-4-phenylbutyl)carbamate (3.24 g, 7.1 mmol) in CH₂Cl₂ (20 mL) at rt was added 15% Dess-Martin periodinane solution in CH₂Cl₂ (23 mL, 10.8 mmol). The mixture was stirred overnight at rt. Satd aq NaHCO₃ (50 mL) was added and the mixture was stirred for 10 min. Solid Na₂S₂O₃ (5 g) was added and stirring was continued for 1 h. The mixture was extracted with CH₂Cl₂ (2×100 mL) and the combined organic layer was washed with brine (35 mL) and dried over Na₂SO₄. Removal of the solvent left an amber oil (3.19 g) which was purified by chromatography on a 40-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (2.32 g, 72%) as a yellow oil. LC-MS Method 1 t_(R)=2.40 min, m/z=470, 468, 348, 346.

Step 5

To a stirred solution of (S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (193 mg, 0.43 mmol) and NH₄OAc (670 mg, 8.6 mmol) in MeOH (15 mL) was added NaCNBH₃ (270 mg, 4.3 mmol). The mixture was heated at reflux for 22 h and concentrated under reduced pressure. The residue was partitioned between 1 M aq NaOH (25 mL) and CH₂Cl₂ (2×50 mL). The combined CH₂Cl₂ layers were washed with brine (15 mL), dried over Na₂SO₄ and concentrated to afford tert-butyl 4-amino-4-phenylbutyl((1S)-1-(4-bromophenyl)ethyl)carbamate (179 mg, 93%) as an oil which was used without further purification. LC-MS Method 1 t_(R)=1.57 min, m/z=449, 447.

Step 6

To a stirred solution of tert-butyl 4-amino-4-phenylbutyl((1S)-1-(4-bromophenyl)ethyl)carbamate (179 mg, 0.40 mmol) in CH₂Cl₂ (5 mL) at rt was added 4 M HCl in dioxane (5 mL). The mixture was stirred for 1 h and concentrated to afford N¹-((1S)-1-(4-bromophenyl)ethyl)-4-phenylbutane-1,4-diamine dihydrochloride (162 mg, 96%). LC-MS Method 1 t_(R)=0.92 min, m/z=349, 347.

Step 7

A stirred solution of N¹—((1S)-1-(4-bromophenyl)ethyl)-4-phenylbutane-1,4-diamine dihydrochloride (19.5 mg, 0.046 mmol) and i-Pr₂NEt (0.10 mL, 0.56 mmol) in CH₂Cl₂ (8 mL) was cooled in an ice bath and solid triphosgene (4.6 mg, 0.015 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO₃ (20 mL), and dried over MgSO₄. Removal of the solvent left a residue (17.5 mg) which was purified by preparative HPLC to afford 1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (1.4 mg, 8%). LC-MS (3 min) t_(R)=2.05 min, m/z=375, 373.

BIOLOGICAL TEST EXAMPLE 1

The inhibition of microsomal preparation of 11β-HSD1 by compounds of the invention was measured essentially as previously described (K. Solly, S. S. Mundt, H. J. Zokian, G. J. Ding, A. Hermanowski-Vosatka, B. Strulovici, and W. Zheng, High-Throughput Screening of 11-Beta-Hydroxysteroid Dehydrogenase Type 1 in Scintillation Proximity Assay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactions were carried out at rt in 96 well clear flexible PET Microbeta plates (PerkinElmer). The assay begins by dispensing 49 μl of substrate solution (50 mM HEPES, pH 7.4, 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 2 mM NADPH and 160 nM [³H]cortisone (1 Ci/mmol)) and mixing in 1 μL of the test compounds in DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 μL of enzyme solution containing microsomes isolated from CHO cells overexpressing human 11β-HSD1 (10-20 μg/ml of total protein) was added, and the plates were incubated for 90 minutes at rt. The reaction was stopped by adding 50 μl of the SPA beads suspension containing 10 μM 18β-glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 μg/ml of anti-cortisol antibody (East Coast Biologics) in Superblock buffer (Bio-Rad). The plates were shaken for 120 minutes at rt, and the SPA signal corresponding to [³H]cortisol was measured on a Microbeta plate reader.

BIOLOGICAL TEST EXAMPLE 2

The inhibition of 11β-HSD1 by compounds of this invention was measured in whole cells as follows. Cells for the assay were obtained from two sources: fully differentiated human omental adipocytes from Zen-Bio, Inc.; and human omental pre-adipocytes from Lonza Group Ltd. Pre-differentiated omental adipocytes from Zen-Bio Inc. were purchased in 96-well plates and were used in the assay at least two weeks after differentiation from precursor preadipocytes. Zen-Bio induced differentiation of pre-adipocytes by supplementing medium with adipogenic and lipogenic hormones (human insulin, dexamethasone, isobutylmethylxanthine and PPAR-gamma agonist). The cells were maintained in full adipocyte medium (DMEM/Ham's F-12 (1:1, v/v), HEPES pH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B, supplied by Zen-Bio, Inc.) at 37° C., 5% CO₂.

Pre-adipocytes were purchased from Lonza Group Ltd. and placed in culture in Preadipocyte Growth Medium-2 supplemented with fetal bovine serum, penicillin, and streptomycin (supplied by Lonza) at 37° C., 5% CO₂. Pre-adipocytes were differentiated by the addition of insulin, dexamethasone, indomethacin and isobutyl-methylxanthine (supplied by Lonza) to the Preadipocyte Growth Medium-2, Cells were exposed to the differentiating factors for 7 days, at which point the cells were differentiated and ready for the assay. One day before running the assay, the differentiated omental adipocytes were transferred into serum- and phenol-red-free medium for overnight incubation. The assay was performed in a total volume of 200 μL. The cells were pre-incubated with serum-free, phenol-red-free medium containing 0.1% (v/v) of DMSO and various concentrations of the test compounds at least 1 h before [³H] cortisone in ethanol (50 Ci/mmol, ARC, Inc.) was added to achieve a final concentration of cortisone of 100 nM. The cells were incubated for 3-4 hrs at 37° C., 5% CO₂. Negative controls were incubated without radioactive substrate and received the same amount of [³H] cortisone at the end of the incubation. Formation of [³H] cortisol was monitored by analyzing 25 μL of each supernatant in a scintillation proximity assay (SPA). (Solly, K.; Mundt, S. S.; Zokian, H. J.; Ding, G. J.; Hermanowski-Vosatka, A.; Strulovici, B.; Zheng, W. Assay Drug Dev. Technol. 2005, 3, 377-384). Many compounds of the invention showed significant activity in this assay.

TABLE OF BIOLOGICAL ASSAY RESULTS Biological Test Example 1 Average % Average % inhibition at 111.1 Compound IC₅₀ Range^(a) inhibition at 100 nM nM EXAMPLE 1 + 13.7 EXAMPLE 2 + 27.2 EXAMPLE 3 + −5.9 EXAMPLE 4 + 22.5 EXAMPLE 5 ++ 94.5 EXAMPLE 6 ++ 89.4 EXAMPLE 7 ++ 90.1 EXAMPLE 8 ++ 100.3  ^(a)++ means IC₅₀ = <100 nM, + means IC₅₀ = 100-1000 nM, # means IC₅₀ > 100 nM, − means IC₅₀ > 1000 nM. PROPHETIC COMPOUNDS

Compound No A¹—R¹ Cy¹ A2 Cy² E R²  1a CHMe Ph bond H bond Ph  2a CHMe 4-Cl—Ph bond H bond i-Pr  3a CHMe Ph bond H bond 2-Me—Ph  4a CHMe Ph bond H bond 4-Me—Ph  5a CHMe Ph bond H bond 4-F—Ph  6a CHMe c-hex bond H bond 4-F—Ph  7a CHMe 3-MeO—Ph bond H bond Ph  8a CHMe 4-HOCH₂—Ph bond H bond Ph  9a CHMe 4-MeO—Ph bond H bond Ph 10a CHMe 4-Me—Ph bond H bond 4-F—Ph 11a CHMe 4-Cl—Ph bond H bond Ph 12a CHMe 3-F—Ph bond H bond 4-F—Ph 13a CHMe 2-F—Ph bond H bond 4-F—Ph 14a CHMe 4-F—Ph bond H bond 4-F—Ph 15a CHMe 4-HOCH₂CH₂—Ph bond H bond Ph 16a CHMe 4-MeOCH₂—Ph bond H bond Ph 17a CHMe 4-Br—Ph bond H bond i-Pr 18a CHMe Ph bond H bond 4-MeS—Ph 19a CHMe 4-HOCH₂—Ph bond H bond 4-F—Ph 20a CHMe 4-MeO—Ph bond H bond 4-F—Ph 21a bond 1,3-C₆H₄ bond Ph bond Ph 22a bond 3-Br—Ph bond H bond Ph 23a CHMe 4-Cl—Ph bond H bond 4-F—Ph 24a CHMe 1,4-C₆H₄ bond c-Pr bond 4-F—Ph 25a bond 1-(t- bond H bond Ph BuOC═O)pyrrolidin- 3-yl 26a bond 1,3-C₆H₄ bond 3-F—Ph bond Ph 27a bond 1,3-C₆H₄ bond 4-F—Ph bond Ph 28a bond 1,3-C₆H₄ bond 2-F—Ph bond Ph 29a CHMe Ph bond 3-pyrazolyl bond Ph 30a bond 2,6-pyridyl bond 4-F—Ph bond Ph 31a CHMe 4-(HOC(Me)₂CH₂—Ph bond H bond Ph 32a bond 1,3-C₆H₄ bond 2-NC—Ph bond Ph 33a CHMe 4-MeO₂C—Ph bond H bond 4-F—Ph 34a CHMe 4-HOC(Me)₂—Ph bond H bond 4-F—Ph 35a CHMe 1,4-C₆H₄ bond 4-pyridyl bond Ph 36a CHMe 1,4-C₆H₄ bond 3-pyridyl bond Ph 37a CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond i-Pr 38a bond 1,3-C₆H₄ bond 2-MeO—Ph bond Ph 39a CHMe 4-Br—Ph bond H bond Ph 40a CHMe 1,4-C₆H₄ bond 2-thienyl bond Ph 41a bond 1,3-C₆H₄ bond 2-Cl—Ph bond Ph 42a bond 1,3-C₆H₄ bond 3-Cl—Ph bond Ph 43a bond 1,3-C₆H₄ bond Ph bond 3-Cl—Ph 44a CHMe 4-F2HCO—Ph bond H bond 4-F—Ph 45a bond 1,3-C₆H₄ bond 2,5-diF—Ph bond Ph 46a bond 1,3-C₆H₄ bond 3,5-diF—Ph bond Ph 47a bond 1,3-C₆H₄ bond 2,4-diF—Ph bond Ph 48a bond 1,3-C₆H₄ bond 4-F—Ph bond Ph 49a CHMe 4-Br—Ph bond H bond 2-thienyl 50a bond 1,3-C6H4 bond 2,4-diF—Ph bond 2-pyridyl 51a bond 2,6-pyridyl bond 4-F—Ph bond 4-F—Ph 52a bond 2,6-pyridyl bond 4-F—Ph bond 2-F—Ph 53a bond 2,6-pyridyl bond 2,4-diF—Ph bond Ph 54a CHMe 3-CF3—Ph bond H bond 4-F—Ph 55a CHMe 4-CF3—Ph bond H bond 4-F—Ph 56a CHEt 4-Br—Ph bond H bond Ph 57a CHMe 1,4-C₆H₄ bond 2-oxo-5-(1,2-dihydropyridyl) bond Ph 58a CHMe 1,4-C₆H₄ bond 1-oxo-3-pyridyl bond Ph 59a CHMe 1,4-C₆H₄ bond 4-F—Ph bond Ph 60a CHMe 1,4-C₆H₄ bond 3-pyridyl bond 4-F—Ph 61a CHMe 1,4-C₆H₄ bond 5-F-3-pyridyl bond Ph 62a CHMe 4-Br—Ph bond H bond 4-F—Ph 63a CHMe 1,4-C₆H₄ bond 4-F—Ph bond 2-thienyl 64a bond 1,3-C₆H₄ bond 2-Cl-4-F—Ph bond Ph 65a bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond Ph 66a bond 1,3-(4-F)C6H3 bond 4-F—Ph bond 4-F—Ph 67a bond 1,3-(4-F)C6H3 bond 4-F—Ph bond 2-F—Ph 68a bond 2,6-pyridyl bond 2,4-diF—Ph bond 4-F—Ph 69a bond 2,6-pyridyl bond 2,4-diF—Ph bond 2-F—Ph 70a CHMe 1,4-C₆H₄ bond 4-morpholinyl bond 4-F—Ph 71a CHMe 1,4-C₆H₄ bond 2-MeO-5-pyridyl bond Ph 72a CHMe 1,4-C₆H₄ bond 1-Me-6-oxo-3-(1,6- bond Ph dihydropyridyl) 73a CHEt 1,4-C₆H₄ bond 4-F—Ph bond Ph 74a CHMe 1,4-C₆H₄ bond 2-Me-4-pyridyl bond 4-F—Ph 75a CHEt 4-Br—Ph bond H bond 4-F—Ph 76a CHMe 1,4-C₆H₄ bond 4-F—Ph bond 4-F—Ph 77a CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond Ph 78a CHMe 1,4-C₆H₄ bond 4-F—Ph bond 3-F—Ph 79a CHMe 1,4-C₆H₄ bond 4-F—Ph bond 2-F—Ph 80a CHMe 1,4-C₆H₄ bond 5-F-3-pyridyl bond 4-F—Ph 81a CHMe 1,4-C₆H₄ bond 5-Me-1,3,4-thiadiazol-2-yl bond 4-F—Ph 82a bond 1,3-C₆H₄ bond 2,6-diCl—Ph bond Ph 83a CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond 2-thienyl 84a bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond 4-F—Ph 85a bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond 2-F—Ph 86a bond 2,6-(5-Cl)-pyridyl bond 4-F—Ph bond 2-F—Ph 87a bond 1,3-(4-F)C₆H₃ bond 2,4-diF—Ph bond 4-F—Ph 88a bond 1,3-(4-F)C₆H₃ bond 2,4-diF—Ph bond 2-F—Ph 89a CHMe 1,4-C₆H₄ bond 5-MeCO-2-thienyl bond Ph 90a CHMe 1,4-C₆H₄ bond 5-MeO-3-pyridyl bond 4-F—Ph 91a CHMe 1,4-C₆H₄ bond 5-(H₂NCHMe)-2-thienyl bond Ph 92a CHEt 1,4-C₆H₄ bond 2,4-diF—Ph bond Ph 93a CHEt 1,4-C₆H₄ bond 4-F—Ph bond 4-F—Ph 94a CHMe 1,4-C₆H₄ bond 5-(HOCHMe)-2-thienyl bond Ph 95a CHMe 1,4-C₆H₄ bond 2,4-diMe-5-thiazolyl bond 4-F—Ph 96a CHMe 1,4-C₆H₄ bond 5-Cl-3-pyridyl bond 4-F—Ph 97a CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond 4-F—Ph 98a bond 1,3-(4-F)C₆H₃ bond 2-Cl-4-F—Ph bond 4-F—Ph 99a bond 2,6-(5-F)-pyridyl bond 2,4-diF—Ph bond 2-F—Ph 100a  CHEt 1,4-C₆H₄ bond 2,4-diF—Ph bond 4-F—Ph 101a  CHMe 1,4-C₆H₄ bond 3-(CF₃)-1-pyrazolyl bond 4-F—Ph 102a  CHMe 1,4-C₆H₄ bond 6-CF₃-3-pyridyl bond 4-F—Ph

 1b CHMe Ph bond H bond Ph  2b CHMe 4-Cl—Ph bond H bond i-Pr  3b CHMe Ph bond H bond 2-Me—Ph  4b CHMe Ph bond H bond 4-Me—Ph  5b CHMe Ph bond H bond 4-F—Ph  6b CHMe c-hex bond H bond 4-F—Ph  7b CHMe 3-MeO—Ph bond H bond Ph  8b CHMe 4-HOCH₂—Ph bond H bond Ph  9b CHMe 4-MeO—Ph bond H bond Ph 10b CHMe 4-Me—Ph bond H bond 4-F—Ph 11b CHMe 4-Cl—Ph bond H bond Ph 12b CHMe 3-F—Ph bond H bond 4-F—Ph 13b CHMe 2-F—Ph bond H bond 4-F—Ph 14b CHMe 4-F—Ph bond H bond 4-F—Ph 15b CHMe 4-HOCH₂CH₂—Ph bond H bond Ph 16b CHMe 4-MeOCH₂—Ph bond H bond Ph 17b CHMe 4-Br—Ph bond H bond i-Pr 18b CHMe Ph bond H bond 4-MeS—Ph 19b CHMe 4-HOCH₂—Ph bond H bond 4-F—Ph 20b CHMe 4-MeO—Ph bond H bond 4-F—Ph 21b bond 1,3-C₆H₄ bond Ph bond Ph 22b bond 3-Br—Ph bond H bond Ph 23b CHMe 4-Cl—Ph bond H bond 4-F—Ph 24b CHMe 1,4-C₆H₄ bond c-Pr bond 4-F—Ph 25b bond 1-(t- bond H bond Ph BuOC═O)pyrrolidin- 3-yl 26b bond 1,3-C₆H₄ bond 3-F—Ph bond Ph 27b bond 1,3-C₆H₄ bond 4-F—Ph bond Ph 28b bond 1,3-C₆H₄ bond 2-F—Ph bond Ph 29b CHMe Ph bond 3-pyrazolyl bond Ph 30b bond 2,6-pyridyl bond 4-F—Ph bond Ph 31b CHMe 4-(HOC(Me)₂CH₂—Ph bond H bond Ph 32b bond 1,3-C₆H₄ bond 2-NC—Ph bond Ph 33b CHMe 4-MeO₂C—Ph bond H bond 4-F—Ph 34b CHMe 4-HOC(Me)₂—Ph bond H bond 4-F—Ph 35b CHMe 1,4-C₆H₄ bond 4-pyridyl bond Ph 36b CHMe 1,4-C₆H₄ bond 3-pyridyl bond Ph 37b CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond i-Pr 38b bond 1,3-C₆H₄ bond 2-MeO—Ph bond Ph 39b CHMe 4-Br—Ph bond H bond Ph 40b CHMe 1,4-C₆H₄ bond 2-thienyl bond Ph 41b bond 1,3-C₆H₄ bond 2-Cl—Ph bond Ph 42b bond 1,3-C₆H₄ bond 3-Cl—Ph bond Ph 43b bond 1,3-C₆H₄ bond Ph bond 3-Cl—Ph 44b CHMe 4-F2HCO—Ph bond H bond 4-F—Ph 45b bond 1,3-C₆H₄ bond 2,5-diF—Ph bond Ph 46b bond 1,3-C₆H₄ bond 3,5-diF—Ph bond Ph 47b bond 1,3-C₆H₄ bond 2,4-diF—Ph bond Ph 48b bond 1,3-C₆H₄ bond 4-F—Ph bond Ph 49b CHMe 4-Br—Ph bond H bond 2-thienyl 50b bond 1,3-C6H4 bond 2,4-diF—Ph bond 2-pyridyl 51b bond 2,6-pyridyl bond 4-F—Ph bond 4-F—Ph 52b bond 2,6-pyridyl bond 4-F—Ph bond 2-F—Ph 53b bond 2,6-pyridyl bond 2,4-diF—Ph bond Ph 54b CHMe 3-CF3—Ph bond H bond 4-F—Ph 55b CHMe 4-CF3—Ph bond H bond 4-F—Ph 56b CHEt 4-Br—Ph bond H bond Ph 57b CHMe 1,4-C₆H₄ bond 2-oxo-5-(1,2-dihydropyridyl) bond Ph 58b CHMe 1,4-C₆H₄ bond 1-oxo-3-pyridyl bond Ph 59b CHMe 1,4-C₆H₄ bond 4-F—Ph bond Ph 60b CHMe 1,4-C₆H₄ bond 3-pyridyl bond 4-F—Ph 61b CHMe 1,4-C₆H₄ bond 5-F-3-pyridyl bond Ph 62b CHMe 4-Br—Ph bond H bond 4-F—Ph 63b CHMe 1,4-C₆H₄ bond 4-F—Ph bond 2-thienyl 64b bond 1,3-C₆H₄ bond 2-Cl-4-F—Ph bond Ph 65b bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond Ph 66b bond 1,3-(4-F)C6H3 bond 4-F—Ph bond 4-F—Ph 67b bond 1,3-(4-F)C6H3 bond 4-F—Ph bond 2-F—Ph 68b bond 2,6-pyridyl bond 2,4-diF—Ph bond 4-F—Ph 69b bond 2,6-pyridyl bond 2,4-diF—Ph bond 2-F—Ph 70b CHMe 1,4-C₆H₄ bond 4-morpholinyl bond 4-F—Ph 71b CHMe 1,4-C₆H₄ bond 2-MeO-5-pyridyl bond Ph 72b CHMe 1,4-C₆H₄ bond 1-Me-6-oxo-3-(1,6- bond Ph dihydropyridyl) 73b CHEt 1,4-C₆H₄ bond 4-F—Ph bond Ph 74b CHMe 1,4-C₆H₄ bond 2-Me-4-pyridyl bond 4-F—Ph 75b CHEt 4-Br—Ph bond H bond 4-F—Ph 76b CHMe 1,4-C₆H₄ bond 4-F—Ph bond 4-F—Ph 77b CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond Ph 78b CHMe 1,4-C₆H₄ bond 4-F—Ph bond 3-F—Ph 79b CHMe 1,4-C₆H₄ bond 4-F—Ph bond 2-F—Ph 80b CHMe 1,4-C₆H₄ bond 5-F-3-pyridyl bond 4-F—Ph 81b CHMe 1,4-C₆H₄ bond 5-Me-1,3,4-thiadiazol-2-yl bond 4-F—Ph 82b bond 1,3-C₆H₄ bond 2,6-diCl—Ph bond Ph 83b CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond 2-thienyl 84b bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond 4-F—Ph 85b bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond 2-F—Ph 86b bond 2,6-(5-Cl)-pyridyl bond 4-F—Ph bond 2-F—Ph 87b bond 1,3-(4-F)C₆H₃ bond 2,4-diF—Ph bond 4-F—Ph 88b bond 1,3-(4-F)C₆H₃ bond 2,4-diF—Ph bond 2-F—Ph 89b CHMe 1,4-C₆H₄ bond 5-MeCO-2-thienyl bond Ph 90b CHMe 1,4-C₆H₄ bond 5-MeO-3-pyridyl bond 4-F—Ph 91b CHMe 1,4-C₆H₄ bond 5-(H₂NCHMe)-2-thienyl bond Ph 92b CHEt 1,4-C₆H₄ bond 2,4-diF—Ph bond Ph 93b CHEt 1,4-C₆H₄ bond 4-F—Ph bond 4-F—Ph 94b CHMe 1,4-C₆H₄ bond 5-(HOCHMe)-2-thienyl bond Ph 95b CHMe 1,4-C₆H₄ bond 2,4-diMe-5-thiazolyl bond 4-F—Ph 96b CHMe 1,4-C₆H₄ bond 5-Cl-3-pyridyl bond 4-F—Ph 97b CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond 4-F—Ph 98b bond 1,3-(4-F)C₆H₃ bond 2-Cl-4-F—Ph bond 4-F—Ph 99b bond 2,6-(5-F)-pyridyl bond 2,4-diF—Ph bond 2-F—Ph 100b  CHEt 1,4-C₆H₄ bond 2,4-diF—Ph bond 4-F—Ph 101b  CHMe 1,4-C₆H₄ bond 3-(CF₃)-1-pyrazolyl bond 4-F—Ph 102b  CHMe 1,4-C₆H₄ bond 6-CF₃-3-pyridyl bond 4-F—Ph

 1c CHMe Ph bond H bond Ph  2c CHMe 4-Cl—Ph bond H bond i-Pr  3c CHMe Ph bond H bond 2-Me—Ph  4c CHMe Ph bond H bond 4-Me—Ph  5c CHMe Ph bond H bond 4-F—Ph  6c CHMe c-hex bond H bond 4-F—Ph  7c CHMe 3-MeO—Ph bond H bond Ph  8c CHMe 4-HOCH₂—Ph bond H bond Ph  9c CHMe 4-MeO—Ph bond H bond Ph 10c CHMe 4-Me—Ph bond H bond 4-F—Ph 11c CHMe 4-Cl—Ph bond H bond Ph 12c CHMe 3-F—Ph bond H bond 4-F—Ph 13c CHMe 2-F—Ph bond H bond 4-F—Ph 14c CHMe 4-F—Ph bond H bond 4-F—Ph 15c CHMe 4-HOCH₂CH₂—Ph bond H bond Ph 16c CHMe 4-MeOCH₂—Ph bond H bond Ph 17c CHMe 4-Br—Ph bond H bond i-Pr 18c CHMe Ph bond H bond 4-MeS—Ph 19c CHMe 4-HOCH₂—Ph bond H bond 4-F—Ph 20c CHMe 4-MeO—Ph bond H bond 4-F—Ph 21c bond 1,3-C₆H₄ bond Ph bond Ph 22c bond 3-Br—Ph bond H bond Ph 23c CHMe 4-Cl—Ph bond H bond 4-F—Ph 24c CHMe 1,4-C₆H₄ bond c-Pr bond 4-F—Ph 25c bond 1-(t- bond H bond Ph BuOC═O)pyrrolidin- 3-yl 26c bond 1,3-C₆H₄ bond 3-F—Ph bond Ph 27c bond 1,3-C₆H₄ bond 4-F—Ph bond Ph 28c bond 1,3-C₆H₄ bond 2-F—Ph bond Ph 29c CHMe Ph bond 3-pyrazolyl bond Ph 30c bond 2,6-pyridyl bond 4-F—Ph bond Ph 31c CHMe 4-(HOC(Me)₂CH₂—Ph bond H bond Ph 32c bond 1,3-C₆H₄ bond 2-NC—Ph bond Ph 33c CHMe 4-MeO₂C—Ph bond H bond 4-F—Ph 34c CHMe 4-HOC(Me)₂—Ph bond H bond 4-F—Ph 35c CHMe 1,4-C₆H₄ bond 4-pyridyl bond Ph 36c CHMe 1,4-C₆H₄ bond 3-pyridyl bond Ph 37c CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond i-Pr 38c bond 1,3-C₆H₄ bond 2-MeO—Ph bond Ph 39c CHMe 4-Br—Ph bond H bond Ph 40c CHMe 1,4-C₆H₄ bond 2-thienyl bond Ph 41c bond 1,3-C₆H₄ bond 2-Cl—Ph bond Ph 42c bond 1,3-C₆H₄ bond 3-Cl—Ph bond Ph 43c bond 1,3-C₆H₄ bond Ph bond 3-Cl—Ph 44c CHMe 4-F2HCO—Ph bond H bond 4-F—Ph 45c bond 1,3-C₆H₄ bond 2,5-diF—Ph bond Ph 46c bond 1,3-C₆H₄ bond 3,5-diF—Ph bond Ph 47c bond 1,3-C₆H₄ bond 2,4-diF—Ph bond Ph 48c bond 1,3-C₆H₄ bond 4-F—Ph bond Ph 49c CHMe 4-Br—Ph bond H bond 2-thienyl 50c bond 1,3-C6H4 bond 2,4-diF—Ph bond 2-pyridyl 51c bond 2,6-pyridyl bond 4-F—Ph bond 4-F—Ph 52c bond 2,6-pyridyl bond 4-F—Ph bond 2-F—Ph 53c bond 2,6-pyridyl bond 2,4-diF—Ph bond Ph 54c CHMe 3-CF3—Ph bond H bond 4-F—Ph 55c CHMe 4-CF3—Ph bond H bond 4-F—Ph 56c CHEt 4-Br—Ph bond H bond Ph 57c CHMe 1,4-C₆H₄ bond 2-oxo-5-(1,2-dihydropyridyl) bond Ph 58c CHMe 1,4-C₆H₄ bond 1-oxo-3-pyridyl bond Ph 59c CHMe 1,4-C₆H₄ bond 4-F—Ph bond Ph 60c CHMe 1,4-C₆H₄ bond 3-pyridyl bond 4-F—Ph 61c CHMe 1,4-C₆H₄ bond 5-F-3-pyridyl bond Ph 62c CHMe 4-Br—Ph bond H bond 4-F—Ph 63c CHMe 1,4-C₆H₄ bond 4-F—Ph bond 2-thienyl 64c bond 1,3-C₆H₄ bond 2-Cl-4-F—Ph bond Ph 65c bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond Ph 66c bond 1,3-(4-F)C6H3 bond 4-F—Ph bond 4-F—Ph 67c bond 1,3-(4-F)C6H3 bond 4-F—Ph bond 2-F—Ph 68c bond 2,6-pyridyl bond 2,4-diF—Ph bond 4-F—Ph 69c bond 2,6-pyridyl bond 2,4-diF—Ph bond 2-F—Ph 70c CHMe 1,4-C₆H₄ bond 4-morpholinyl bond 4-F—Ph 71c CHMe 1,4-C₆H₄ bond 2-MeO-5-pyridyl bond Ph 72c CHMe 1,4-C₆H₄ bond 1-Me-6-oxo-3-(1,6- bond Ph dihydropyridyl) 73c CHEt 1,4-C₆H₄ bond 4-F—Ph bond Ph 74c CHMe 1,4-C₆H₄ bond 2-Me-4-pyridyl bond 4-F—Ph 75c CHEt 4-Br—Ph bond H bond 4-F—Ph 76c CHMe 1,4-C₆H₄ bond 4-F—Ph bond 4-F—Ph 77c CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond Ph 78c CHMe 1,4-C₆H₄ bond 4-F—Ph bond 3-F—Ph 79c CHMe 1,4-C₆H₄ bond 4-F—Ph bond 2-F—Ph 80c CHMe 1,4-C₆H₄ bond 5-F-3-pyridyl bond 4-F—Ph 81c CHMe 1,4-C₆H₄ bond 5-Me-1,3,4-thiadiazol-2-yl bond 4-F—Ph 82c bond 1,3-C₆H₄ bond 2,6-diCl—Ph bond Ph 83c CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond 2-thienyl 84c bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond 4-F—Ph 85c bond 2,6-pyridyl bond 2-Cl-4-F—Ph bond 2-F—Ph 86c bond 2,6-(5-Cl)-pyridyl bond 4-F—Ph bond 2-F—Ph 87c bond 1,3-(4-F)C₆H₃ bond 2,4-diF—Ph bond 4-F—Ph 88c bond 1,3-(4-F)C₆H₃ bond 2,4-diF—Ph bond 2-F—Ph 89c CHMe 1,4-C₆H₄ bond 5-MeCO-2-thienyl bond Ph 90c CHMe 1,4-C₆H₄ bond 5-MeO-3-pyridyl bond 4-F—Ph 91c CHMe 1,4-C₆H₄ bond 5-(H₂NCHMe)-2-thienyl bond Ph 92c CHEt 1,4-C₆H₄ bond 2,4-diF—Ph bond Ph 93c CHEt 1,4-C₆H₄ bond 4-F—Ph bond 4-F—Ph 94c CHMe 1,4-C₆H₄ bond 5-(HOCHMe)-2-thienyl bond Ph 95c CHMe 1,4-C₆H₄ bond 2,4-diMe-5-thiazolyl bond 4-F—Ph 96c CHMe 1,4-C₆H₄ bond 5-Cl-3-pyridyl bond 4-F—Ph 97c CHMe 1,4-C₆H₄ bond 2,4-diF—Ph bond 4-F—Ph 98c bond 1,3-(4-F)C₆H₃ bond 2-Cl-4-F—Ph bond 4-F—Ph 99c bond 2,6-(5-F)-pyridyl bond 2,4-diF—Ph bond 2-F—Ph 100c  CHEt 1,4-C₆H₄ bond 2,4-diF—Ph bond 4-F—Ph 101c  CHMe 1,4-C₆H₄ bond 3-(CF₃)-1-pyrazolyl bond 4-F—Ph 102c  CHMe 1,4-C₆H₄ bond 6-CF₃-3-pyridyl bond 4-F—Ph ^(a)Cy¹ = 1,3-C₆H₄ means

Cy¹ = 1,4-C₆H₄ means

Cy¹ = 1,3-(4-F)C₆H₃ means

Cy¹ = 2,6-(5-Cl)-pyridyl means

The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of cortisol is effective in treating a disease state. Thus, the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome, infertility and hypergonadism. In addition, the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients.

The disclosed compounds can be used alone (i.e. as a monotherapy) or in combination with another therapeutic agent effective for treating any of the above indications. The pharmaceutical compositions can comprise the disclosed compounds alone as the only pharmaceutically active agent or can comprise one or more additional pharmaceutically active agents.

A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃, comprise a pharmaceutically acceptable salt of a compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃ or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore. Alternatively, a pharmaceutical composition of the invention may comprise a compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃ or a pharmaceutical salt thereof as the only pharmaceutically active agent in the pharmaceutical composition.

A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃, comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore.

The compositions of the invention are 11β-HSD1 inhibitors. Said compositions contain compounds having a mean inhibition constant (IC₅₀) against 11β-HSD1 of below about 1,000 nM; preferably below about 100 nM; more preferably below about 50 nM; even more preferably below about 5 nM; and most preferably below about 1 nM.

The invention includes a therapeutic method for treating or ameliorating an 11β-HSD1 mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃ or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof of composition thereof. As used herein, “treating” or “treatment” includes both therpaeutic and prophylactic treatment. Therapeutic treatment includes reducing the symptoms associated with a disease or condition and/or increasing the longevity of a subject with the disease or condition. Prophylactic treatment includes delaying the onset of a disease or condition in a subject at risk of developing the disease or condition or reducing the liklihood that a subject will then develop the disease or condition in a subject that is at risk for developing the disease or condition.

An embodiment of the invention includes administering an 11β-HSD1 inhibiting compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃ or composition thereof in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma. Agents for the treatment of diabetes include insulins, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitizone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase®/Glynase® (glyburide, Pfizer), and Glucotrol®/Glucotrol XL® and (glipizide, Pfizer); meglitinides, such as Prandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase®/Glucophase XR® (metformin HCl, Bristol Myers Squibb) and Glumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs, GLP-1 analogs; DPP-IV inhibitors; PTB-1B inhibitors; protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase kinase-3 beta inhibitors; glucose-6-phoshatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors, and alpha-glucosidase inhibitors, such as Precose®/Glucobay®/Prandase®/Glucor® (acarbose, Bayer) and Glyset® (miglitol, Pfizer). Agents for the treatment of dyslipidemia and cardiovascular disease include statins, fibrates, and ezetimbe. Agents for the treatment of hypertension include alpha-blockers, beta-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitor, aldosterone-receptor antagonists, or endothelin receptor antagonist. Agents for the treatment of obesity include orlistat, phentermine, sibutramine and rimonabant.

An embodiment of the invention includes administering an 11β-HSD1 inhibiting compound of Formula I, I₁-I₂₆, Ia₁₋₃-Ij₁₋₃ or composition thereof in a combination therapy with one or more other 11β-HSD1 inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); and Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb).

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can either be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from about one to about seventy percent of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium caboxymethylcellulose, a low-melting wax, cocoa butter, and the like. Tablets, powders, cachets, lozenges, fast-melt strips, capsules and pills can be used as solid dosage forms containing the active ingredient suitable for oral administration.

For preparing suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first-melted and the active ingredient is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions for oral administration can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

The pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of, for example, tablets, powders, and capsules in vials or ampules. Also, the unit dosage form can be a tablet, cachet, capsule, or lozenge itself, or it can be the appropriate amount of any of these in packaged form.

The quantity of active ingredient in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000.0 mg, preferably from about 0.1 mg to about 100 mg. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill in the art. Also, the pharmaceutical composition may contain, if desired, other compatible therapeutic agents.

In therapeutic treatment or as a method-of-use as an inhibitor of 11β-HSD1 or an inhibitor in the production of cortisol in the cell, the active ingredient is preferably administered orally in a solid dosage form as disclosed above in an amount of about 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily.

All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually designated as having been incorporated by reference. It is understood that the examples and embodiments described herein are for illustrative purposes only, and it will be appreciated that the invention is susceptible to modification, variation and change without departing from the proper scope or fair meaning of the appended claims. 

1. A compound of Formula (I)

wherein R is

R¹ is (a) absent or (b) is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl, wherein each is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R⁴, R⁴⁰—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino; A¹ is (a) a bond, or (b) (C₁-C₃)alkylene, CH₂CH₂O, wherein the oxygen is attached to Cy¹, or CH₂C(═O), wherein the carbonyl carbon is attached to Cy¹; Cy¹ is aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl; (C₁-C₆)alkylcarbonyl; (C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl, di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminosulfonyl, di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl and di(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; provided that if (a) t is 2 and Q is O or CH₂ or t is 1 and Q is 0, (b) A¹ is CH₂ optionally substituted with R₁ and (c) A² is a bond, then Cy² is meta or para to the ring atom of Cy¹ that is bonded to A¹ and the aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl, represented by Cy¹ is not substituted with bromine, iodine, amino, halo(C₁-C₆)alkyl at a ring atom ortho to the carbon atom bounded to A¹; A² is (a) a bond, O, S or NR⁴; or (b) (C₁-C₃)alkylene or (C₁-C₂)alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo; Cy² is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl; (C₁-C₆)alkylcarbonyl; (C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl} aminocarbonyl, di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminosulfonyl, di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}-aminocarbonyl(C₁-C₆)alkyl and di(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; provided that if (a) t is 1; (b) Q is 0, (c) A^(i) is CH₂ optionally substituted with R¹ and (d) Cy^(i) is phenyl then A²Cy² is not NHR⁴ or optionally substituted heterocyclyl; provided that if (a) A¹ is CH₂CH₂O; (b) Cy¹ is phenyl and (c) A² is CH₂ then Cy¹ is not heterocyclyl substituted with oxo; R^(1a) and R^(1b) are each independently selected from (a) hydrogen or (b) (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl which are optionally substituted with up to three groups independently selected from fluorine, hydroxy, (C₁-C₃)alkoxy and H₂NC(═O); A is straight or branched (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl, optionally substituted with up to 4 groups independently selected from fluorine, cyano, oxo, R⁴, —OH R⁴O—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴SO₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, heterocyclylamino (wherein the heterocyclyl portion is optionally substituted by alkyl, haloalkyl or oxo); heteroarylamino (wherein the heteroaryl portion is optionally substituted by alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); arylamino (wherein the aryl portion is optionally substituted by alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and cycloalkylamino (wherein the cycloalkyl portion is optionally substituted by alkyl, haloalkyl or oxo); t is 1, 2 or 3; Y is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl; n is 0, 1 or 2; E is (a) a bond or (b) (C₁-C₃)alkylene or (C₁-C₂)alkylenyloxy, wherein the O is attached to R², each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo; provided that if Q is NH, then ER² is not (C₁-C₆)alkyl or benzyl; R² is (C₁-C₆)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, nitro, hydroxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio, (C₃-C₆)cycloalkylhio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkylhio, halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl, halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, H₂NCO, H₂NSO₂, (C_(r) C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl, (C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl, heterocyclsulfonyl, (C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy, (C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyl; (C₁-C₆)alkylcarbonyl; (C₃-C₆)cycloalkylcarbonyl, (C₃-C₆)cycloalkylaminocarbonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl, di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminosulfonyl, di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl, {(C₃-C₆)cycloalkyl} {(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl and di(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; wherein the 1 to 4 substituents for the group represented by R² are additionally selected from: amino, cyano, carboxy, (C₁-C₆)alkoxycarbonyl and hydroxy(C₁-C₆)alkyl, when E is bond or (C₁-C₃)alkylene, t is 1 and Q is O or CH₂, provided that ER² is not CH₂Cl, CH₂OH, CHO or CH₂O phenyl; provided that when (a) t is 2; (b) E is bond and (c) R² is phenyl, then R² is not substituted with (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy; provided that when (a) A¹ is bond; (b) R¹ is absent; (c) Cy¹ is phenyl; (d) A² is bond (e) Cy² is H and (f) E is bond, then R² is not unsubstituted phenyl; provided that when (a) t is 1; (b) Q is NR⁵; (c) A¹ is bond; (d) R¹ is absent; (e) Cy¹ is optionally substituted phenyl; (f) A² is bond; (g) Cy² is H then ER² is not unsubstituted (C₁-C₆) alkyl; Q is O, NR⁵ or CH₂; each R⁴ is independently selected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl; and each R⁵ is independently H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
 2. The compound of claim 1, wherein the compound is of Formula (I₁)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 3-14. (canceled)
 15. The compound of claim 1 wherein the compound is of Formula (I₁₄)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
 16. The compound of claim 15 wherein the compound is of Formula (I₁₅)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
 17. The compound of claim 15 wherein the compound is of Formula (I₁₆)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
 18. The compound of claim 15 wherein the compound is of Formula (I₁₇)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 19-50. (canceled)
 51. The compound of claim 1, wherein:

R is R¹ is absent or is methyl or ethyl; A¹ is a bond or CH₂; Cy¹ is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy and 2-hydroxy-2-methylpropoxy; A² is a bond, O or OCH₂CO; Cy² is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl or piperazinyl optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl or tetrazolyl; n is 0; E is a bond or CH₂; R² is phenyl or pyridyl optionally substituted with one group selected from halo, methyl, methylthio or (4-morpholino)methyl. 52-61. (canceled)
 62. The compound of claim 1, wherein R is

R^(1a) is methyl or ethyl; R^(1b) is methyl or hydrogen; A is methyl, ethyl, isopropyl or t-butyl; n is 0; E is a bond or CH₂; and R² is phenyl, thienyl or pyridyl each optionally substituted with halo or methyl.
 63. The compound of claim 1, wherein R is

R^(1a) is methyl; R^(1b) is hydrogen or methyl; A is methyl or t-butyl; n is 0; E is a bond; and R² is phenyl or 4-fluorophenyl. 64-65. (canceled)
 66. (canceled)
 67. The compound of claim 1 wherein the compound is of Formula (Ia₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 68-69. (canceled)
 70. The compound of claim 1 wherein the compound is of Formula (Ib₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 71-72. (canceled)
 73. The compound of claim 1 wherein the compound is of Formula (Ic₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 74-75. (canceled)
 76. The compound of claim 1 wherein the compound is of Formula (Id₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 77-78. (canceled)
 79. The compound of claim 1 wherein the compound is of Formula (Ie₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 80-81. (canceled)
 82. The compound of claim 1 wherein the compound is of Formula (If₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 83-84. (canceled)
 85. The compound of claim 1 wherein the compound is of Formula (Ig₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 86-93. (canceled)
 94. The compound of claim 1 wherein the compound is of Formula (Ij₂)

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 95-99. (canceled)
 100. A compound selected from the group consisting of: (S)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one; (R)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one; (R)-3-(naphthalen-1-yl)-6-phenyl-1,3-oxazinan-2-one; 3-(3-Bromo-phenyl)-6-(2-chloro-phenyl)-[1,3]oxazinan-2-one; 1-((1S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-phenylpiperidin-2-one; 4(-4-fluorophenyl)-1-((1S)-1-(4-methoxylphenyl)ethyl)piperidin-2-one; 3-((1S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one; 4-phenyl-1-((1S)-1-phenylethyl)-1,3-diazepan-2-one; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
 101. A method of treating a subject with a disease associated with the activity or expression of 11β-HSD1, comprising the step of administering to the subject an effective amount of the compound of claim
 1. 102. A method of inhibiting 11β-HSD1 activity comprising the step of administering to a subject in need of such treatment an effective amount of a compound of claim
 1. 103. A method of claim 101, wherein the disease associated with the activity or expression of 11β-HSD1, is diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome, infertility, hypergonadism, tuberculosis, leprosy or psoriasis.
 104. A method of claim 101, wherein the disease associated with the activity or expression of 11β-HSD1, is diabetes, cardiovascular disease, anxiety or depression, glaucoma or osteoporosis. 105-106. (canceled)
 107. A pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) the compound of claim 1; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. 108-111. (canceled) 